Cases semester 1

Question 1

1. Is it possible that someone:
   
   • a) has glucosuria at a serum glucose concentration of 5 mmol/l?
   • b) does not have glucosuria at a serum glucose concentration of 15 mmol/l?

Answer 1

• a) Yes, if there is an issue with glucose reabsorption in the proximal convoluted tubule, known as “renal glucosuria”. This can be seen in “Fanconi syndrome”, a disorder with multiple possible congenital or acquired causes leading to impaired reabsorption of various molecules from the kidney.
• b) Yes, if there is a problem with glomerular filtration, such as decreased GFR via renal artery obstruction or diabetic nephropathy.
  
  • normal GFR = 120-130 ml/min
  • end-stage diabetic kidney = 5-10 ml/min
  • tubular glucose reabsorption threshold @ normal GFR = 10 mmol/l , but at a low GFR, reabsorption of a higher concentration of glucose can be performed
  • pt with severely ↓ GFR should be put on dialysis and kidney transplant list

Question 2

2. A 15-year-old girl has been losing weight in spite of having a good appetite , and she feels tired lately. She has been admitted to a hospital for vomiting , being dizzy and disoriented .

• Laboratory findings:
  
  • urine glucose: strongly positive
  • ketone bodies: positive
  • blood glucose: 28.5 mmol/l
  • blood pH: 7.1
  • serum K+: 5.4 mmol/l

What is your diagnosis, and what is to be done with her?

Answer 2

• Current condition: Diabetic ketoacidosis, as indicated by the blood + urine glucose (diabetic), ketone bodies (keto-) and low PH/high K + (-acidosis!).
• Underlying cause: Type 1 Diabetes Mellitus , as indicated by the patient’s age, weight loss (rather than gain seen in type 2), and blood/urine glucose (> 11 mM random blood glucose indicates DM without need for further testing). Type 1 can be confirmed by checking for islet cell/insulin/glutamic acid decarboxylase autoantibodies.
• Symptom explanations:
  
  • tiredness due to “fasting” cells (no insulin to stimulate glucose uptake)
  • weight loss due to use of muscle protein & TAG (glycerol) from adipose tissue for gluconeogenesis
  • dizziness/disorientation via dehydration (glucose → osmotic diuresis)
  • nausea via acidosis → vomiting helps excrete acid
• Hyperkalemia occurs because: ↓ glucose in cells → ↓ Na/K-ATPase activity → ↑ EC K + and metabolic acidosis → renal H + excretion → renal K + reabsorption
• Treatment: IV fluids and insulin (2-3 units/hr), both slowly to avoid complications
  
  • GLUT2/3 transport in neurons can become dysfunctional with fast ↓ glucose so a 5 mM/day reduction is best
  • cerebral edema can occur with fast ↑ fluids
  • pH monitoring and K+ monitoring is important, as there may be a hypokalemic rebound when Na/K-ATPases begin to function again, requiring K + infusion
  • older T1DM patient may require bicarbonate for pH normalization

Question 3

3. A 56 year-old man who used to be healthy complains of polyuria.

• Laboratory findings:
  
  • fasting blood glucose: 7.3 mmol/l,
  • fasting blood glucose a week later: 7.6 mmol/l.

What is your diagnosis, and what would you do with him?

Answer 3

• Diabetes mellitus, a fasting blood glucose > 7 mmol/l confirms this.
  
  • Can check autoantibodies to confirm which type (presence of Abs would suggest LADA), but it is likely type 2 because of his age and the not-so-high glucose level.
• Can be treated with diet, exercise and oral antihyperglycemics (sulfonylureas, etc.)
• Should also check for retinopathy , peripheral neuropathy , other risk factors for atherosclerosis (smoking, htx), and nephropathy (proteinuria, etc.)

Question 4

4. A 60 year-old woman, weighing 90 kg. Fasting blood glucose concentration: 6.9 mmol/l. Neither

glucose nor ketone bodies are found in her urine.

• The results of oral glucose tolerance test:
  
  • fasting value: 6.4 mmol/l
  • 2h value: 8.5 mmol/l

What is your diagnosis, and what would you advise to her?

Answer 4

• Impaired Glucose Tolerance (IGT) - because of her 2-hr OGTT value >7.8 but <11 .
• 20-25% of IGT/IFG patients later develop T2DM
• Patient should lose weight if obese (90 kg is high unless she’s tall), reduce dietary carbohydrates, exercise and have her blood glucose checked regularly.

Question 5

5. Laboratory findings of a person:

• fasting blood glucose: 6.2 mmol/l
• Oral glucose tolerance test was performed on another occasion:
  
  • fasting value: 6.3 mmol/l
  • 2h value: 6.5 mmol/l.

What is the diagnosis, and what is the clinical significance of it?

Answer 5

• Impaired Fasting Glucose (IFG) - just indicates higher risk of developing T2DM

Question 6

6. What are your options to check the glucose metabolism of your diabetic patient, to decide if the current treatment needs to be changed or not?

Answer 6

• Home glucose test kit - a “strip” method, not as accurate as a lab, but a record kept of these values is useful.
• Fasting blood glucose + HbA1c taken at the clinic every 3 months with a target HbA1c of 6-7%
  
  • ​However, fasting glucose tests provide an indication of your current glucose levels only, whereas the HbA1c test serves as an overall marker of what your average levels are over a period of 2-3 months.
• Yearly check-ups for the various diabetic complications … neuro-, nephro-, retinopathy
• (another glycosylated serum protein “fructosamine” can be checked but only indicates avg. glucose levels of past 2 weeks)

Question 7

7. A diabetic patient treated with insulin has a fasting blood glucose concentration of 6.4 mmol/l. No glucose (I assume they mean urinary) was detected on the morning of the examination.

The Hb-A1C level is 10 % (normal value: 3–6 %).

Do you think the control of glucose concentration was acceptable in the last 1–2 months?

Answer 7

No, because the target HbA1c is 6-7% for treated diabetics. Either the patient is not following a proper diet or the treatment needs to be adjusted.

(The fasting value btwn 6-7 mM also would indicate a need for OGTT if the patient had not already been diagnosed as DM.)

Question 8

8. A type 1 diabetic man has been eating very little for the last couple of days, due to a febrile illness, so he decided to stop administering his insulin. He checked his blood glucose, because he felt worse and worse, and was surprised to see, that it was more than 20 mM.

What is the explanation?

Answer 8

A type 1 DM patient who stops insulin administration will have intense gluconeogenesis due to extremely low endogenous insulin production.

Febrile illness will also have gluconeogenic effects via increased cortisol + cytokines seen in acute infections.

Question 9

9. A diabetic man treated with insulin skipped his late evening meal before going to bed,

without any change in his insulin administration. He has been sweating a lot during the

night, and glucose has been detected in his urine in the morning.

What is the explanation for this?

Answer 9

• Paradox/Somogyi Effect - no meal + insulin = hypoglycemia → sympathetic activation → sweating + ↑ insulin antagonist hormones (cortisol/glucagon/GH/catecholamines/T3/T4) → gluconeogenesis → hyperglycemia + morning glucosuria
• treatment is actually carb intake and/or less insulin administration
• (not sure about that part… that’s what Tunde said… i guess carbs → ↓ insulin antagonists/gluconeogenesis and then ↓ blood sugar? but seems weird … also Wikipedia says the Somogyi effect might be fake…)

Question 10

10. A man with type 1 diabetes, cooperating very well with his physician, keeps his diet and insulin administration very precisely. He is an employee of a bank, and currently attends a team building training, a several-day-long survival tour causing significant physical exertion. The man, who is known to be reserved, starts shouting and quarreling with his coworkers, then he begins to sweat, quiver and develops cramps.

What do you think is the explanation of his behaviour?

Answer 10

• Hypoglycemia due to the physical exertion without either lowering insulin or increasing carb intake.
  
  • Exercise → ↑ GLUT4 translocation → ↑ glucose uptake in muscle → ↓ blood glucose
• Low blood sugar → sympathetic activation → sweating
• Direct hypoglycemic CNS effects → mood alteration

Question 11

11. A woman was admitted to the hospital with the complaint of recurrent seizures. Her fasting blood glucose level is 2.7 mmol/l.

What can cause these symptoms? What tests would you perform to establish the diagnosis?

Answer 11

• if diabetic - over-administration of insulin
• if not diabetic - insulinoma / alcohol (via ↓ NAD + → ↓ gluconeogenesis)/ fever / sepsis / Addison’s / hypothyroidism
• Tests:
  
  • imaging - for insulinoma, 80% in pancreas, 20% in GI tract
  • C-peptide - will be ↓ in insulin overdose, or high in insulinoma
  • ACTH stimulation test - to check for Addison’s

Question 12

12. A breast-fed infant was admitted to the hospital with weight loss, vomiting and jaundice.

Blood glucose level is somewhat low. Glucose is not, but a reducing substance is detectable in the urine.

What is the likely diagnosis?

Answer 12

• Galactosemia - a deficiency of galactose-1-phosphate uridylyltransferase enzyme (GALT)
• Inability to convert galactose to glucose → weight loss
• Fermentation of galactose in gut → vomiting, distension, pain
• Galactose metabolite galactitol builds up in liver + spleen → hepatosplenomegaly + jaundice
• The “reducing substance” in the urine is galactose.
• Can be treated by excluding dietary galactose (milk).

Question 13

13. A small boy gets regularly sick after eating sugar containing foods: he is sweating, feels dizzy, vomits. He does not eat sweets for this reason. These symptoms were shown to be caused by reactive hypoglycemia, on examination.

What is the likely diagnosis?

Answer 13

• Fructose intolerance - lack of aldolase B enzyme (fructose-1-P → glyceraldehyde + dihydroxyacetone-P)
• leads to “phosphate trapping” via accumulation of F-1-P and inhibited glucose/ATP production

Question 14

1. After finding high lipid concentrations in the serum, what tests would you employ to confirm or exclude the secondary causes of hyperlipidemia?

Answer 14

ODACHECHGK

• Obesity/Metabolic Syndrome - more FFA → more liver TAGs → ↑ VLDL → ↑ LDL ↓ HDL
  
  • measure waist circumference, BMI, fasting glucose, BP, TAGs + HDL
• DM - ketone/FFA efflux from adipose → liver TAGs + VLDL → ↑ LDL / ↓ HDL
  
  • perform the WHO diagnostic algorithm (random glucose → fasting glucose → OGTT)
  • type I pt only develops dyslipidemia if untreated; type II usually has dyslipidemia
  • in type II, LPL activity ↓ so chylomicrons + VLDL ↑
• Alcoholism - ↓ NAD + → ↓ β-oxidation → ↑ TAG synthesis
  
  • measure GGT
  • moderate alcohol intake inhibits CETP → ↑ HDL
• Cushing - ↑ glucocorticoids → ↑ VLDL synthesis → ↑ serum LDL (mild)
  
  • measure serum cortisol
• Hypothyroidism - synthesis + activity of LDL-R ↓ → serum IDL/LDL ↑
  
  • check TSH, T3, T4
• Estrogen Treatment/Pregnancy - ↑ VLDL synth and ↓ hepatic lipase activity → ↑ TG/Chol.
  
  • should only be treated with diet
• Cholestasis - see ↑ “Lipoprotein X” (LP-X) an abnormal low density lipoprotein
• Hepatic Disease - primary biliary cirrhosis + obstructive liver diseases → ↑ cholesterol
  
  • ASAT, ALAT, albumin and GGT can be measured
  • LP-X also seen
• Glycogen Storage Disease - ↓ G-6-phosphatase (von Gierke) → adipose FFA efflux ↑ → TAG synthesis ↑
• Kidney Disease - proteinuria → hypoalbuminemia → ↑ protein synth (thus apoproteins) → lipids ↑
  
  • measure albumin, protein content of urine
  • in kidney transplant, immunosuppression glucocorticoids → ↑ lipids

Question 15

2. The laboratory parameters of a male person having normal blood pressure, BMI 23 kg/m2 are:

• serum TG: 1.5 mmol/l
• serum LDL cholesterol:4.4 mmol/l
• serum CRP: 5 mg/l

What is the risk of CHD for this person? What are the risk factors of atherosclerosis?

Answer 15

• TGs and BMI are normal
• LDL is high (>3.4 mmol/l)
• CRP is within normal range, but still above the 3.0 mg/L cut-off for high risk of CHD development
• Because of higher CRP and high LDL, patient is at high risk for developing CHD.
• Atherosclerosis Risk Factors:
  
  • Modifiable: smoking, exercise, hypertension, weight, diet, stress
  • Non-modifiable: age, sex, genetics, diseases (DM, renal disease … can be treated but not cured)

Question 16

3. A 45 year old man has the following parameters:

• waist circumference: 110 cm
• BP: 140/90 mmHg
• HDLC: 0.9 mmol/l
• fasting blood glucose: 6.3 mmol/l

What is your opinion about the risk of CHD for this person?

Answer 16

• waist large (>102 cm), BP high, HDL low (<1.0 mM), glucose high (btwn 6-7 needs OGTT)
• patient is at high risk for CHD
• meets 4 of the criteria for metabolic syndrome (waist, BP, HDL + glucose)
  
  • other metabolic syndrome criteria = high TAGs

(**Central obesity High blood pressure … Fasting glucose Metabolic syndrome - elevated risk**)

Question 17

4. A 35 year old man wanted to be screened for possible ischemic heart disease because his father died early from a heart attack. The patient was not obese and was a nonsmoker. On examination his blood pressure was normal and the only abnormality was tendon xanthoma arising from the Achilles tendons. An ECG taken at rest was normal but ischemic changes developed on exercise. Fasting lipids: serum cholesterol 8.7 mmol/l, triglyceride 1.1 mmol/l. What is the most likely diagnosis and how can you confirm it?

Answer 17

• High serum cholesterol (>5.2 mM) but normal TGs (< 1.7 mM) this is a “ type IIa “ phenotype hyperlipidemia, suggestive of familial hypercholesterolemia

2 pics

• Diagnosis can be confirmed via genetic testing (LDL-R or Apo-B mutation), fibroblast culture (to count LDL-Rs on cell surface), or just differential diagnosis via serum lipids, presence of xanthomas and familial tendency toward similar findings.
• Heterozygotes for the autosomal dominant LDL-R mutation may have CHD as young adults, whereas homozygotes are at risk for childhood CHD + xanthomas.
• Treatment with statins (HMG-CoA reductase inhibitors) is recommended.

(**Primary Hyperlipoproteinemias Heterozygot (Homozygos is very rare, accelerated AS)**)

Question 18

5. A middle-aged man saw his family doctor, because he got rashes. On examination he was

found to have extensive yellowish papules, with an erythematous base, on his buttocks and

elbows and orange-yellow discoloration of the palmar creases.

Fasting lipids: serum cholesterol 7.6 mmol/l, triglyceride 8.1 mmol/l.

What is your diagnosis?

Answer 18

• High serum cholesterol (>5.2 mM) and very high TGs (>1.7 mM).
• Discolored palmar crease = xanthoma striatum palmare
• Lipid increase pattern + xanthomas indicative of familial type III hyperlipoproteinemia
  
  • due to an autosomal recessive Apo E mutation (a defective “ApoE2” form)
  • results in increased TGs and IDL
  • also known as “familial dysbetalipoproteinemia” or “remnant hyperlipidemia” because of Apo E’s role in removal of VLDL remnants (IDL)
• Can test for the mutated gene, must have two mutated alleles.
• Xanthomas + atherosclerosis develop due to increased accumulation of cholesterol within scavenging macrophages

(**Hyperlipidemia type III**)

Question 19

1. A 61 year-old man lost 8 kg during the last 4 months. He complains of pruritus and frequent dull epigastric pain. He has noted dark urine , but light stools lately. He has jaundice . The gallbladder is palpable, but non-tender.

Laboratory results:

serum bilirubin: 310 μmol/l, mostly direct

urine Ubg: negative

ASAT: 82 U/l

ALAT: 91 U/l

alkaline phosphatase: 540 U/l

prothrombin time: INR = 2.6

What is the cause of his jaundice? What further tests do you consider?

Answer 19

• Serum bilirubin is very high (>17 umol/l) and mostly direct, indicating direct hyperbilirubinemia (no issue with UDP-glucuronyl transferase)
• Lack of Ubg suggests total obstruction of bilirubin secretion into the GI tract
• ASAT/ALAT are high (>45 U/l) and ALP is very high (>150 U/l) indicating liver damage and significant obstruction , respectively
• Prothrombin time is long (>1.2 INR) indicating liver disease and/or biliary obstruction ( → improper vitamin K absorption → no γ-carboxylation of clotting factors)
• Weight loss in an elderly patient indicates malignancy (in younger pt, DM / anorexia / malabsorption / hyperthyroid)
• A palpable, non-tender gallbladder is the Courvoisier sign for pancreatic carcinoma (the enlarged head elevates the GB)
• Dark urine = direct bilirubin ; light stool = no stercobilin ; both indicate obstruction
• Endoscopic retrograde cholecysto-pancreatography
  
  • administer contrast to bile + pancreatic ducts to observe size of tumor
• Imaging (US, CT, MRI) to observe size of tumor + presence of metastases
• Administer IV vitamin K to resolve prothrombin time

Question 20

2. An icteric woman has the following laboratory parameters:

• serum indirect bilirubin: 54 μmol/l
• serum direct bilirubin: 5,1 μmol/l
• urine bilirubin: negative
• ASAT: 19 U/l
• ALAT: 22 U/l
• LDH: 720 U/l
• Ht: 0.33 l/l
• plasma haptoglobin and hemopexin concentrations are significantly decreased

What is the cause of her jaundice?

Answer 20

• indirect bilirubin is high; direct is normal indicating increased hemolysis with normal UDP-glucuronyl transferase function
• ASAT/ALAT are normal indicating no liver damage
• Urine bilirubin is absent (only conjugated bilirubin enters urine)
• LDH is high indicating hemolysis (specifically LDH1 from RBCs)
• Ht is low (<0.37 l/l) indicating anemia/hemolysis
• Haptoglobin/hemoplexin are proteins which bind broken down Hb in the blood, ↓ indicates intravascular hemolysis
• So the cause of jaundice is intravascular hemolysis , but the cause of hemolysis is unknown and must be determined.
• Can check for viral / autoimmune (RA/SLE) / allergic (penicillin) / etc. causes

Question 21

3. A 38 year-old man, who regularly drinks alcohol. He has never been ill before (acute!) , but he has grown icteric in the last couple of days. He has a temperature , and is a little anemic. His liver is palpable an inch below the ribs, it is slightly tender.

Laboratory results:

• urine color: dark brown
• serum total bilirubin: 150 μmol/l
• ASAT: 160 U/l
• ALAT: 60 U/l
• GGT: 490 U/l
• MCV: 103 fl

What is the cause of his jaundice?

Answer 21

• Dark brown urine indicates bilirubinuria (specifically direct, only direct goes to urine)
• Total bilirubin is high (>17 umol/l)
• ASAT/ALAT are elevated, with ASAT higher, indicating alcoholic liver damage
  
  • alcohol is a mitochondrial toxin → release of mitochondrial “mASAT”
• GGT is elevated (>60 U/l) indicating alcoholic liver damage
• MCV is high (>95 fl) indicating macrocytic anemia
  
  • due to vitamin B deficiency common in alcoholics via inflammatory malabsorption + malnutrition
• acute symptoms indicate this is not cirrhosis → acute alcoholic hepatitis is the cause of jaundice

Question 22

4. A 47 year-old man has been on hemodialysis for 5 years before he got his kidney transplantation . He has little body hair , a large, protruding belly , slim extremities and gynecomastia.

Laboratory results:

• ASAT: 85 U/l
• ALAT: 76 U/l
• prothrombin time: INR = 2.7; it does not change after vitamin K administration
• albumin: 28 g/l
• K+: 3.3 mmol/l
• Ht: 0.36

What is the most likely diagnosis?

Answer 22

• equally, but not extremely elevated ASAT/ALAT (>45 U/l) indicate chronic non-alcoholic liver damage
• elongated PTR (1.2 INR) unresponsive to vit. K indicates liver damage → coag. factor deficiency
• decreased albumin (< 35 g/l) indicates liver dysfunction
• dialysis is a risk factor for iatrogenic hepatitis
• low K + (<3.5 mM) probably via:
  
  • ascites (“protruding belly”) → ↓ circulating fluid volume → activation of RAAS in kidney → ↑ aldosterone → ↑ K + excretion
• low Ht (<0.4 l/l) via anemia , common in liver disease
• “effeminate” body constitution (↓ hair, breasts, slim limbs) indicates liver dysfunction
• This is most likely cirrhosis via a chronic iatrogenic hepatitis from dialysis.
  
  • Blood transfusions are common after dialysis, and can lead to hepatitis C infection (according to Hamar).

Question 23

5. A 38 year-old woman complains of recurrent, sharp pain in the right upper quadrant of her abdomen. She has been vomiting , has fever and jaundice .

Laboratory results:

• serum bilirubin: 50 μmol/l, mostly direct
• Ubg: negative
• ASAT: 180 U/l
• alkaline phosphatase: 640 U/l

What is the cause of her symptoms, and how can you prove the diagnosis?

Answer 23

• High, mostly direct bilirubin (>17 umol/l) indicates obstructive jaundice
• Negative Ubg also indicates obstructive jaundice (no bilirubin → GI tract)
• ASAT elevation (>45 U/l) indicates liver damage
• ALP elevation (>150 U/l) indicates obstruction
• Sharp RUQ pain indicate possible gallstones
• Vomiting and fever indicate possible cholecystitis
• Prove the possibility of cholelithiasis with abdominal ultrasound .

Question 24

6. A 25 year-old man has been icteric for a few days.

His laboratory values:

• serum indirect bilirubin: 47 μmol/l
• serum direct bilirubin: 4 μmol/l
• ASAT: 18 U/l ALAT: 23 U/l
• alkaline phosphatase: 66 U/l
• Ht: 0.48
• Hb: 162 g/l

What is the cause of his jaundice?

What further tests are necessary?

Answer 24

• Indirect bilirubin increase with normal direct indicates indirect hyperbilirubinemia (conjugation enzyme issue)
• Normal ASAT/ALAT/ALP indicate no liver damage/obstruction
• Normal Ht/Hb (>0.4 l/l and >135 g/l) indicates no hemolysis
• This is Gilbert syndrome , slightly decreased UDP-g transferase activity. Only slightly increased indirect bilirubin is seen, with no other abnormal findings.
• Test : No further tests are necessary, but Tunde says you can do this (if you hate your patient):
  
  • Have the patient fast (<1000 kcal/day) for 2 days and then measure indirect bilirubin. If it has doubled from your initial measurement, this confirms Gilbert’s syndrome.
  • (Acute stress can cause otherwise “silent” Gilbert’s to show symptoms. This test simulates that effect.)

Question 25

7. A 32 year-old man has been complaining of fatigue, malaise and a temperature for a week. His liver is palpable ¾ of an inch below the ribs, it is a bit tender.

His laboratory results:

• serum indirect bilirubin: 28 μmol/l
• serum direct bilirubin: 24 μmol/l
• Ubg: increased
• ASAT: 870 U/l
• ALAT: 1180 U/l
• alkaline phosphatase: 310 U/l

What is the most likely diagnosis, and how can you prove it? What further tests are necessary?

Answer 25

• Equal direct + indirect bilirubin elevation → hepatocellular jaundice
• Ubg increase → not obstructed , Ubg production in GI tract
• ASAT/ALAT/ALP elevation → liver damage
  
  • High ALAT/ASAT ratio particularly indicates viral hepatitis as the cause of damage
• Palpable, tender liver + fatigue/malaise/fever → acute hepatitis
• Check for Hep A/B/C antigens/antibodies
  
  • If A → check family
  • If B/C → check sexual partners + recheck patient after 6-8 months
    
    • If antigens still high after 6-8 months, start antiviral therapy to avoid chronic hepatitis + cirrhosis

Question 26

8. A 28 year-old woman. She is complaining of fatigue , malaise and nausea .

• serum total bilirubin: 45 μmol/l
• ALAT: 220 U/l
• alkaline phosphatase: 200 U/l
• γ-globulins: 33 g/l (↑)
• RF and ANA: positive

What is the most likely diagnosis, and what tests should be done?

Answer 26

• Increased total bilirubin (>17 umol/l) → hyperbilirubinemia
• Elevated ALAT/ALP (>45 U/l) → liver damage , possibly obstructive
  
  • Some complaints could be due to pregnancy (fatigue, malaise, nausea) and ALP is increased in pregnancy. A more specific test for liver damage would be GGT .
• RF/ANA → SLE
• γ-globulin increase indicates excess circulating antibodies
• This is most likely systemic lupus erythematosus causing an autoimmune hepatitis.
• Check other antibodies: anti-Smith antigen (RNA-binding protein) and anti-cardiolipin
• It is possible, but rare, for Hep B/C to induce the formation of RF/ANA, so must rule these out.

Question 27

9 . A 30 year-old woman, who is 164 cm tall, her body weight is 81 kg . She saw her doctor, because she had noted a yellow discoloration of her skin accompanied by itching . She mentions she has had unpleasant gastrointestinal symptoms after meals for a long time: feeling full , having nausea . Physical examination reveals: yellow skin and sclera , spleen is not palpable , liver enlarged by an inch. The right upper quadrant of her abdomen is clearly sensitive on palpation.

Laboratory findings:

• serum bilirubin: 150 μmol/l
• urine bilirubin: positive
• Ubg: decreased
• ASAT: 53 U/l
• alkaline phosphatase: 710 U/l
• GGT: 390 U/l

What is the most likely diagnosis?

Answer 27

• High bilirubin + urine bilirubin → hyperbilirubinemia , of conjugated type b/c only conjugated gets to urine
• Ubg decrease → obstruction , no bilirubin to GI tract
• ASAT is slightly increased → mild liver damage
• ALP is very high (>150 U/l) → obstruction
• GGT is high (>60 U/l) → obstruction
• Obstructive jaundice has two common possible causes: malignancy or cholelithiasis
• In a young (30 yr old) and overweight (81 kg @ 164 cm) patient, gallstones are the most likely cause
• Perform abdominal ultrasound.

Question 28

10. A newborn baby is admitted to the hospital with a complaint of increasing jaundice. The serum bilirubin is 160 μmol/l.

What can be the cause of the jaundice if this bilirubin is mainly:

1. direct, or
2. indirect reacting?

Answer 28

1. Causes of direct hyperbilirubinemia:
   
   • Infection - hepatitis or any other infection can ↓ liver function
   • Biliary atresia - improper development of bile ducts
   • Dubin-Johnson Syndrome - AR mutation of canalicular MRP2 → ↓ hepatic excretion of bilirubin glucuronide (liver appears black)
   • Rotor Syndrome - AR mutation of OATP1B (organic anion transporting polypeptide) proteins for hepatic uptake of of bilirubin
2. Causes of indirect hyperbilirubinemia:
   
   • Physiological jaundice - before birth glucuronyltransferase is downregulated in the fetus to keep bilirubin unconjugated and thus able to pass through the placenta and not accumulate in the fetus; it takes some time to fully function after birth b
   • Erythroblastosis fetalis - via Rh incompatibility → hemolysis
   • Gilbert’s Disease - low UDP-g transferase function, often asymptomatic unless stressed
   • Crigler-Najjar - 2 types: total or partial lack of UDP-glucuronosyl transferase
     
     • severe form can lead to kernicterus (bilirubin in brain) → brain damage
       
       • only treatment is liver transplant
     • phenobarbital can induce the enzyme in the less severe form
   • Phototherapy can be used to solubilize excess dermal bilirubin in neonatal jaundice.

Question 29

1. A 60 year-old man complains of weight loss, diarrhea alternating with constipation. The patient is pale (anemic). What tests would you perform?

Answer 29

• Weight loss, diarrhea/constipation + anemia in pt of this age → GI malignancy
  
  • Other possibilities for weight loss in elderly include depression , but with these GIsymptoms, tumor is likely
• Alternating constipation + diarrhea due to obstruction via tumor → formation of large, dry stoolmass → osmotic activity of mass eventually draws a lot of water from bowel → diarrhea
• Can perform an occult blood test - aka “hemoccult” test, recommended as yearly GI cancerscreening for pts above 45
• Can also check GI tumor markers :
  
  • CEA (carcinoembryonic antigen) - not specific, but often elevated incolorectal/gastric/pancreatic and other carcinomas
  • CA 19-9 (carbohydrate antigen) - AKA Sialyl-Lewis A, elevated in colon/pancreaticcancers
• Check hematocrit for the anemia: tumor may bleed directly or consume RBC co-factors
• Perform endoscopy and colonoscopy.
• Irrigoscopy - patient drinks contrast agent + GI tract is visualized; area where contrast not seenmay be tumor
• Can do various imaging studies (MRI, CT, etc.) for metastases

(**Colon cancer constipation alternating diarrhea is due to blockage in the GI, build up of . .. + bacteria will digest and thats why diarrhea.Check for blood in … Colonoscopy - to see the inside, if suspecting in the microscopy, biopsy is takenCT examination gives s good idea but no biopsy can be taken.**)

Question 30

2. A patient with symptoms of chronic alcoholism complains of recurrent abdominal pain, meteorism. He has lost weight in the past few months, his stools are voluminous, difficult to flush.

serum Ca: 2.1 mmol/l

prothrombin time INR: 2.6; normalized after vitamin K administration

serum glucose (fasting): 12 mmol/l

ALP: 264 U/l

albumin: 40 g/l

fecal elastase: decreasedabdominal

ultrasound: enlarged pancreas

What is your diagnosis? What other tests would you do?

Answer 30

• “Meteorism” (bloating) and big, difficult to flush stool → issues digesting fat → steatorrhea
• Slightly low serum Ca⁺⁺ (<2.2 mmol/l) via two mechanisms:
  
  • decreased vitamin D absorption via fat malabsorption
  • “saponification” of FFAs with Ca ++ in the damaged pancreas
• Prothrombin time elongated (>1.2 INR) fixed by vit. K → fat/vit. k malabsorption
• Very high fasting glucose (>7 mmol/l) → decreased insulin production
• High ALP (>150 U/l) → bone resorption to accommodate ↓ Ca ++
  
  • Hamar: ALP increase here is mild, so obstruction is not the likely cause of pancreatitis.
• Normal albumin (35-50 g/l) → inflammation is not acute
• Fecal elastase decrease → decreased pancreatic exocrine activity
  
  • Elastase is synthesized equimolar with other pancreatic enzymes + its level in fecesindicates exocrine activity (decrease indicates chronic pancreatitis)
• Enlarged pancreas on US → pancreatitis
• Probably chronic pancreatitis because of normal albumin (would be lowered in acute phase rxn).
  
  • Main cause of this is alcoholism , but may also be autoimmune.
• Need to rule out pancreatic cancer so must perform endoscopic retrogradecholecysto-pancreatography (ERCP).

(**meteorism - a lot …Chronic pancreatitisLack of lipase - lipid digestion -> Mal absorption of lipids -> Mal absorption of vit KDiabetes may develop ..Elastase - produced in the pancreas (many others are digested)Ca++. a bit lower - vit K is lower, we can assume that Vit D is also low (bone…)IV secretin - chole… than sucking the produced pancreatic juice (disadvantage - tube is needed)Pancreolauryl test**)

Question 31

3. A patient complains of intense periumbilical pain of sudden onset. His blood pressure is low, the pulse is fast, he is sweating and has nausea. There is no defense on physical examination of the abdomen.

Laboratory results:

• ESR: 42 mm/h
• WBC: 11 G/l
• serum α-amylase: 1800 U/l
• urine α-amylase: increased
• serum lipase: increased
• serum urea: 10 mmol/l
• serum creatinine: 90 μmol/l
• serum Ca: 1.9 mmol/l
• serum albumin: 30 g/l
• fasting blood glucose: 6.5 mmol/l.

What is your diagnosis? What other tests would you perform?

Answer 31

• High ESR (>20 mm/h) → inflammation
  
  • In inflammation, increased serum fibrinogen causes RBCs to stick together and form“rouleaux” which settle faster via increased density.
• High WBC (>10 G/l) indicates inflammation / immune reaction
• High α-amylase (>180 U/l), urine amylase and serum lipase indicates pancreatitis
• Serum urea is borderline high → slightly impaired kidney function○ can be via redistribution of blood flow in early shock (low BP, high HR)
• Creatinine is normal (40-130 uM)
• Ca⁺⁺ is low (<2.2 mM) indicating impaired fat digestion → ↓ vitamin D○ In pancreatitis, autodigestion via lipase → “saponification” of FFAs + Ca → ↓ Ca⁺⁺ (elongated QT on ECG)
• Serum albumin is low (<35 g/l) indicating acute inflammation
• Fasting glucose is high (>6.0 mM) → low insulin secretion, but not actually…
  
  • ~90% islets must be destroyed before glucose ↑
  • in acute inflammation, stress hormone elevation → high gluconeogenesis
• Periumbilical or “belt-like” pain is typical of pancreatitis.
• Low BP + tachycardia point to the beginnings of shock.
  
  • Shock Index = HR / Systolic BP … should be around 0.5-0.66 … >1 indicates probableshock (means ↑ HR ↓ BP)
• This is acute pancreatitis , because of the high ESR, low albumin and high serum/urine pancreaticenzymes.
• Imaging studies (US, CT or MRI) can be done to confirm pancreatic enlargement
• Commonly caused by cholelithiasis or alcohol and greasy foods.
  
  • Alcohol dehydrates pancreatic secretions + need for more lipase to digest foods →viscous secretions back up in pancreatic ducts → autolysis + inflammation
• Treatment is symptomatic: NPO (“nil per os”, no food/drink by mouth) and painkillers

(**ESR: 42 mm/h. - suggesting inflammationWBC: 11 G/l - slightly elevatedserum α-amylase: 1800 U/l - highurine α-amylase: increasedserum lipase: increased*** acute pancreatitis (if lipase is not elevated the others could be a result of salivary glands)intense periumbilical pain of sudden onset - typical for acute pancreatitisserum urea: 10 mmol/l - slightly elevated (kidney failure due to shock)serum creatinine: 90 μmol/l serum Ca: 1.9 mmol/l (hypocalcemia - know the reason and the ECG sign)serum albumin: 30 g/l (low, maybe due to inflammatory reaction)fasting blood glucose: 6.5 mmol/l (any major inflammation/stress may cause)Acute pancreatitis.other tests: no need for further (amylase, lipase is enough)- other examinations are needed in order to check if the patient is getting better or worse (serum CRP - Everyday), which type of pancreatitis (adematus, necrotic) - imaging (US only size)(CT - will see necrotic area)**)

Question 32

4. A 35 year-old man complains of heartburn and occasional regurgitation of sour material in his mouth, mostly in the morning especially if leaning down. These symptoms were provoked by drinking beer the evening before. Findings of an esophago-gastro-duodenoscopy: the proxymal part of the esophagus is normal, but the distal part is hyperemic with erosions. The cardia is loose, the antrum is hyperemic in patches. The bulbus and the postbulbar duodenum is normal.

What is your diagnosis?

What further test and treatment should be considered?

Answer 32

• This is GERD (gastroesophageal reflux disease).
• Main causes are: LES insufficiency, diaphragmatic hernia, acid overproduction, obesity, 3rd trimester pregnancy
• Tests : diagnosis of GERD is usually made based on symptoms, but certain tests can be done if acase does not respond well to therapy, or prior to surgery
  
  • Esophageal manometry - done prior to surgery, a nasogastric catheter is lowered intothe stomach and then slowly withdrawn as it measures pressure changes
  • Endoscopy with biopsy - can culture a sample from ulcer to check for H. pylori
  • Urea Breath Test - to check for H. pylori
• Treatment :
  
  • If H. pylori positive → triple therapy : clarithromycin, amoxicillin and PPI○ Patient can avoid eating/drinking before lying down and avoid alcohol/coffee and spicyfood.
  • PPIs such as omeprazole can reduce gastric acidity

(**GEGDother tests: - H.pylori infection (Biopsy+culture)/(urea exhalation test)treatment - PPI, tossing weight, avoid carbo drinks**)

Question 33

5. A 45 year old patient complains of maldigestion, increasing abdominal pain and weakness. Abdominal discomfort occurs shortly after meals or alcohol ingestion. Laboratory results:

• Haemoccult: +
• anemia

What tests would you do, what are the treatment options?

Answer 33

• Positive hemoccult and anemia in 45 yr. old w/ abd. pain → maybe malignancy, but…
• Pain shortly after meals/alcohol → peptic ulcer is mostly likely
• May also be IBD (Crohn’s / UC)
• Tests :
  
  • Endoscopy + biopsy to check for presence of ulcer and culture it for H. pylori and alsoto differentiate between ulcer and cancer
  • Urea Breath Test - isotope-labelled urea solution is swallowed, if H. pylori is present, itsurease breaks down urea into isotope-labelled CO 2 which is detected in patient’s breath
  • If the above tests are negative for ulcer / H. pylori, use the tests mentioned in the nextquestion for IBD.
• Treatment :
  
  • If H. pylori positive → triple therapy : clarithromycin, amoxicillin and PPI

(**Abdominal discomfort occurs shortly after meals - typical for … (ulcer)Haemoccult: + (peptic ulcer have a tendency to bleedother: gastroscopy+biopsy (h.pylori, gastric cancer biopsy)Differential: - Drugs NSAID - ….**)

Question 34

6. What tests would you perform if you suspect your patient has an autoimmune inflammatory bowel disease?

Answer 34

• If patient has not already reported visible blood in stool → hemoccult
• Colonoscopy/endoscopy with biopsy - always done for suspected UC or Crohn’s
• If nothing is found via colonoscopy/endoscopy, can perform capsule endoscopy
• Stool culture + microscopy to rule out microbial/helminthic infection
• Systemic inflammatory markers such as CRP or ESR
• Antibodies can be tested such as ASCA (anti-S. cerevisiae, common in Crohn’s) and p-ANCA (common in UC)

(**Chron’s / Colitis ulcerosa (diagnosis: endoscopy [biopsy: histologically they are very different])Chron’s - transmural | Colitis ulcerosa - only mucosaChron’s - inf. anywhere |. (ileitis terminalis)| Colitis ulcerosa - Rectum/**)

Question 35

7. A 30 year-old man complains of recurrent abdominal pain usually accompanied with diarrhea. These symptoms occur after the ingestion of fresh dairy products or alcohol.

What may be the cause of these complaints? What tests would you do?

Answer 35

• This is lactose intolerance which can be worsened by alcohol, because it decreases lactase activity.
• Tests :
  
  • Lactose Hydrogen Breath Test - patient swallows a lactose solution and their breath ischecked every 20-30 mins for 2-3 hours against a baseline measurement for largeincreases in hydrogen gas
  • Blood Glucose Test - lactose malabsorbers will generally see less of an increase inblood glucose after ingesting lactose
  • Stool Acidity Test - for infants b/c they don’t cooperate with

(**Lactose intolerance(HBT)Alcohol - inhibits enzyme activity (worsen the symptoms)**)

Question 36

1. A 45-year-old man seeks evaluation for weakness, fatigue, decrease of libido and loss of body weight. Laboratory tests reveal low plasma levels of ACTH and TSH. What is the most likely diagnosis and which laboratory tests would be the most appropriate for the patient?

Answer 36

• Decreased libido → low FSH/LH → low testosterone + ↓ spermatogenesis
• Weakness and fatigue can be explained by low ACTH/TSH → low cortisol + T3/4
• Tests :
  
  • Imaging - MRI for to check for adenoma compressing + compromising pituitary function
  • Complex Stimulatory Test:
    
    • Give GnRH - look for ↑ FSH/LH
    • Give TRH - look for ↑ TSH + PRL
    • Give insulin - look for ↓ glucose → ↑ GH
• Treatment :
  
  • TRH to increase TSH; CRH to increase ACTH; insulin to increase GH
  • Surgically remove adenoma if found
• The most likely diagnosis is panhypopituitarism , due to an adenoma, or some other cause.
• Other possible causes for pituitary hypofunction:
  
  • Vascular lesions:
    
    • ex: Sheehan/Simmond’s syndrome - pituitary ischemic necrosis via intrapartum hemorrhagic hypovolemia
  • Infection
  • Trauma / surgery / irradiation
  • ” Empty sella syndrome “ - pituitary flattens + sella is full of CSF, rarely hormonally consequential
  • Hypothalamic lesions ○ Developmental abnormalities + perinatal asphyxia
• The usual progression of hormone loss is:
  
  • GH → LH-FSH → ACTH → TSH → PRL→ ADH

(**Any endocrine: imaging studies Lab test: deficiency of the enzymes are ……. stimulation tests**)

Question 37

2. In a 29-year-old woman complaining of amenorrhea, plasma PL is found elevated in association with low FSH and LH levels. Estrogen excretion is decreased. GnRH stimulation test was performed on three consecutive days. The first two tests were negative but after the third test a normal response was detected in plasma FSH and LH. How do you interpret the result of the test and what is the most likely diagnosis?

Answer 37

• Amenorrhea can be primary (no period/secondary sex characteristics by age 14) or secondary (disruption of a previously normal menstrual cycle, via pregnancy/thyroid disease/prolactinoma)
• Increased prolactin → ↓ GnRH → ↓ FSH / LH → ↓ estrogen
• Chronically low GnRH levels causes downregulation of GnRH-R on gonadotropic cells of the pituitary, so several GnRH stimulation tests were required to raise FSH/LH levels.
• Tests : directed at finding the source of high prolactin
  
  • MRI : to check for a prolactinoma , which make up 40% of pituitary tumors
  • Visual Field Testing - check for bitemporal hemianopsia, commonly caused by pituitary tumors affecting the optic chiasm → blindness in the outer halves of L/R visual fields
    
    • Often irrelevant in prolactinomas because they are commonly “microadenomas” too small to affect the optic chiasm.
  • TSH / T3/4 - hyperthyroidism can increase prolactin
• Most likely diagnosis is prolactinoma, since PRL is elevated.
• Treatment can consist of surgical removal of the adenoma or bromocriptine (dopamine agonist) to decrease PRL secretion.

(**prolactin secreting adenoma Therapy why repeat? - if hormone is lacking for a long time, the target organ may be atrophied**)

Question 38

3. A 44-year-old man complains of impotence and galactorrhea. He has gynecomastia. Plasma PL is very high, FSH and LH are lower than normal. Plasma testosterone and urinary 17-ketosteroid excretion are decreased. After TRH or chlorpromazine stimulation there is only a minimal increase in plasma PL. What is the most likely diagnosis and what other tests would you perform?

Answer 38

• Galactorrhea and gynecomastia are common in hyperprolactinemia in men.
• Impotence is due to decreased testosterone via ↑ PRL → ↓ GnRH → ↓ FSH/LH
• TRH/Chlorpromazine (dopamine antagonist) stimulation test is used to determine if the source of prolactin hypersecretion is regulated by dopamine. Endocrine tumors often are not regulated by the same means as the normal source of the hormone, so seeing only a minimal increase here further supports the possibility of an adenoma.
• Most likely diagnosis is prolactinoma
• Tests : directed at finding the source of high prolactin
  • MRI : to check for a prolactinoma , which make up 40% of pituitary tumors
  • Visual Field Testing - check for bitemporal hemianopsia, commonly caused by pituitary tumors affecting the optic chiasm → blindness in the outer halves of L/R visual fields
    
    • Often irrelevant in prolactinomas because they are commonly “microadenomas” too small to affect the optic chiasm.
  • TSH / T3/4 - hyperthyroidism can increase prolactin

Question 39

4. A 51-year-old man seeks evaluation for blurring of vision and headache. He has coarse facial features and enlarged extremities. The determination of which hormone would be the most straightforward in the patient? What other diagnostic procedure(s) would you order?

Answer 39

• IGF-1 is the hormone to check, because GH secretion is pulsatile and thus hard to measure accurately.
• Blurring of vision / headache → probably a GH-secreting adenoma compressing the optic chiasm and increasing pressure in the sella turcica.
• Coarse facial features and enlarged extremities indicate acromegaly, which is caused by ↑ GH.
• Can perform a GH suppression test:
  
  • Normally insulin → ↓ glucose → ↑ GH
  • In this test we administer glucose and, in a healthy patient, see a drop in GH.
  • In patients with inappropriate GH secretion we may see less of a drop, no drop or a paradoxical increase.
• MRI can be done to verify the presence of an adenoma.
• Other pituitary hormones should be checked to assess the “mass effect” of the adenoma on the rest of the pituitary gland.
• Check visual field for possibility of bilateral hemianopsia.
• Treatment: can include surgical removal of the tumor, dopamine agonists (bromocriptine/cabergoline) or somatostatin analogues (octreotide) to ↓ GH secretion, GH-R antagonists or radiation (if surgery can not remove entire mass)

Question 40

5. In a 35-year-old woman, after the third delivery, lactation fails to start. She complains of loss of body weight and amenorrhea. Low voltage is found in her EKG tracing. Plasma levels of anterior pituitary hormones are very low . FT4 and FT3 are low. After TRH stimulation test neither TSH nor PL increase . Serum cholesterol level: 8.6 mmol/l. Is the problem primary, secondary or tertiary?

Answer 40

• In this case, a primary problem would be in the thyroid and TSH levels would be high, which they are not. A tertiary problem would be at the level of the hypothalamus, and TRH stimulation would resolve it.
• Since TRH does not resolve the issue, the problem is most likely in the pituitary and is thus a secondary issue.
• Amenorrhea (via low FSH/LH) and overall low ant. pituitary hormones → panhypopituitarism
• Third delivery and failed lactation → Sheehan’s syndrome:
  
  • Hyperplasia/-trophy of lactotroph cells during pregnancy → increased O₂ demand without increased blood supply plus ant. pituitary is supplied by a low-pressure portal circulation.
  • If peripartum hemorrhage leads to hypovolemia → ischemic pituitary necrosis
• First sign is usually agalactorrhea via low PRL, followed by amenorrhea via low FSH/LH.
• Weight loss is caused by loss of insulin antagonists (↓ ACTH → ↓ cortisol) and resulting hypoglycemia (which overcomes the weight gain effects of hypothyroidism)
• Lack of TSH → low T3/T4 → pericardial myxedema → low ECG voltage
• Cholesterol is high because T3 stimulates LDL-R production and stimulates lipolysis , thus lowering serum cholesterol, and T3 is lacking here. (normal serum cholesterol: 3.6-5.2 mmol/l)

Question 41

6. A 37-year-old man complains of intense thirst (anadipsia) which commenced 7 days before. He drinks 5–6 l water a day, preferentially chilled water. His urine output is 6 l/24 h , the density is 1.004 kg/l . He is subjected to a water deprivation test with a duration of 8 h. During the test period he voids 4 l urine and the density does not exceed 1.005 kg/l in any of the collected fractions. What is the most likely diagnosis and which test would be the most effective in the differential diagnosis?

Answer 41

• Most common cause of sudden onset polyuria is diabetes mellitus, but this urine is low density (<1.01 kg/l) so does not contain a lot of glucose.
• A blood sugar measurement would be the first step in differential diagnosis.
• Normally a water deprivation test stimulates ADH secretion → lower urine volume + higher density, which is not seen in this patient, so this is probably diabetes insipidus.
• Next step in differential diagnosis is determining the type:
  
  • Central DI - lack of ADH production + secretion by hypothalamus/pituitary
  • Nephrogenic DI - lack of ADH-R response in kidney, usually due to chronic renal disorders (kidney failure, etc.)
  • To determine which type, administer ADH and check if urine volume ↓ / density ↑
    
    • If central DI is determined, should check the hypothalamus for tumors/metastases via MRI.

Question 42

7. A 50-year-old woman complains of polyuria . She drinks 6–8 l water a day. Serum Na⁺: 138 mmol/l, urine output: 8 l/24 h, density: 1.004 kg/l. After salt loading urine volume decreases and the density increases. What is the most likely diagnosis?

Answer 42

• Salt loading is IV administration of 1.2% NaCl - 0.9% is isotonic, so this ↑ Na + levels
  
  • ↑ serum osmolarity should induce ADH secretion
• Since salt loading helped, presumably this is not diabetes insipidus.
• Primary Psychogenic Polydipsia
  
  • seen in OCD, schizophrenia, etc. or more mildly in people who just want to “cleanse”, etc.
• Note: ADH measurement would not be accurate here because the patient’s high intake of water would decrease serum osmolarity and thus ↓ ADH, possibly leading to false diagnosis of DI.

Question 43

1. The laboratory parameters of a 42-year-old man are: plasma prolactin and cortisol decreased, urinary 17-ketosteroid excretion is decreased , plasma prolactin level is not influenced by TRH . The administration of hCG increased the urinary excretion of 17-ketosteroids . What is the possible diagnosis?

Answer 43

• PRL and cortisol ↓ indicate pituitary hypofunction (cortisol via ↓ ACTH)
• 17-ketosteroid ↓ indicates secondary gonadal hypofunction , probably via ↓ FSH/LH
• Since PRL is not increased by TRH, pituitary hypofunction is confirmed.
• Since hCG is able to increase 17-ketosteroids via androgenic action on the testis, primary gonadal hypofunction is ruled out.
• Diagnosis is panhypopituitarism (AKA Simmonds’ disease)
  
  • Treatment is via administration of hormones made by target organs of pituitary hormones: T4 for thyroid; cortisol for adrenal gland; testosterone in males/ estrogen in females; GH only in children; FSH/LH only for ovulation induction

Question 44

2. The laboratory parameters of a 19-year-old man are: plasma testosterone decreased , FSH and LH are elevated , urinary 17-ketosteroid excretion is decreased. The administration of hCG did not increase plasma testosterone level or the urinary excretion of 17-ketosteroids. What is the possible diagnosis?

Answer 44

• This is primary hypogonadism since neither the physiological FSH/LH ↑, nor the exogenous hCG administration induces normalization of testosterone levels.
• In an older patient, this might be a normal consequence of aging. Since this patient is young, it may be due to a chromosomal abnormality such as Klinefelter’s syndrome (47, XXY) or a childhood viral infection resulting in testicular inflammation (orchitis).
• Treatment is lifelong testosterone supplementation.

Question 45

3. The laboratory parameters of a 42-year-old man are: plasma testosterone increased significantly , FSH and LH are barely detectable, urinary excretion of androgens is increased . The right testis is enlarged . What is the possible diagnosis?

Answer 45

• Increased testosterone with low gonadotropins indicates primary hypergonadism
• Unilateral testis enlargement indicates an androgen-secreting tumor (“seminoma”) in the testis.
• Decreased FSH/LH is due to negative feedback from the increased testosterone levels.
• Hormone-secreting tumors of the testicles may produce female hormones. In this case of an hCG-secreting tumor, pregnancy tests may show up positive for males.

Question 46

1. A patient with apparent symptoms of hypothyroidism. What laboratory tests would be the most appropriate to perform?

Answer 46

• TSH - measured first and if normal, problem is likely not in the thyroid, because negative feedback mechanisms usually alter TSH levels in case of hyper-/hypothyroidism.
  
  • if TSH high and T3/T4 low - primary hypothyroidism , check antibodies:
    
    • anti-TPO antibody - in most Hashimoto’s and Graves’ patients
    • anti-TSH-R antibody - stimulating form in all Graves’ and “blocking” form in some Hashimoto’s and later-stage Graves’ patients
    • anti-TG antibody - in most Hashimoto’s and some Graves’ (30%)
  • if TSH low and T3/T4 low - secondary hypothyroidism:
    
    • administer TRH: if it doesn’t help, the problem is in the pituitary; if it does, the problem is hypothalamic (“tertiary hypofunction”, very rare)
• Hypothyroid symptoms :
  
  • fatigue, feeling cold, constipation, depression, weight gain, hair loss
  • myxedema - ↑ TSH stimulates fibroblasts to deposit more glycosaminoglycans → osmotic edema
  • hoarse voice, poor memory/concentration
  • ascites, pleural/pericardial effusion

(**fT3; fT4 to check for hypfunction look for the reason If TSH is low - secondary; tertiary (TRH stimulation test is needed)**)

Question 47

2. A 40 year old woman seeks evaluation for subfebrility and diarrhea commenced 2–3 weeks before. Blood glucose: 6.6 mmol/l. Blood pressure: 160/85 mmHg, heart rate: 120/min. Serum TSH: 0.15 mU/l (decreased), FT4: 60 pmol/l (elevated), TRAb titer elevated, TPO-antibody positive. What is the most likely diagnosis? What other test would you order to specify your diagnosis?

Answer 47

• This is probably Graves’ disease as indicated by symptoms (↑ temperature, diarrhea, ↑ BP) and lab values (↑ glucose, ↑ FT4, TRAb, anti-TPO and ↓ TSH)
• Other tests: check for presence, structure and function of nodules via…
  
  • Ultrasound - can distinguish between solid nodes and cystic nodes (cystic are less frequently malignant)
  • Scintigraphy - administer radioactive iodine and/or technetium; iodine is preferentially taken up by the thyroid; Graves’ disease shows diffuse “warmth”; adenomas show a more focused “warm” spot; “cold” nodules have higher chance of malignancy
  • Cytology - fine needle aspiration of nodular cells can confirm or rule out malignancy
• Exophthalmos seen in Graves’ and other hyperthyroid conditions does not go away upon administration of thyrostatic drugs; retrobulbar CT deposits must be surgically removed (extra info from Tunde)
• Elevated blood glucose here does not necessitate OGTT, because it can be explained by ↑ T4
• Note : There are sometimes “blocking” TRAbs seen in Hashimoto’s, so since we have anti-TPO here it could also be argued that this may be the first stage of Hashimoto’s, characterized by hyperthyroidism as cell destruction releases stored T3/4.
• Note : Apparently Mozes really likes to ask about the method for testing serum TSH and all you have to say is “supersensitive” and he is happy. The reference range for TSH is in mU/l (milli-Units per liter). Many of the other things using these “international units” (i.e. ASAT/ALAT) are in U/l, so TSH is clearly present in very low amounts in the blood, requiring very sensitive measurement techniques.

(**Hyperfunction (increased metabolic rate) Grave’s disease CT?? gram, diffused**)

Question 48

3. A 42 year old woman developed diffusely enlarged, painless thyroid glands. Total T4 is decreased, thyroid uptake of radioiodine is low. ECG reveals low voltage and bradycardia. The thyroid autoimmunity panel demonstrates the presence of TgAb and TPO-Ab. What is the most likely diagnosis? Is this condition characterized by a hypo or hyperfunction of the thyroid gland?

Answer 48

• This is probably Hashimoto’s thyroiditis as indicated by the decreased T4 and presence of TG and TPO antibodies.
• Painless goiter is indicative of, but not specific for, Hashimoto’s. It can also be seen in iodine deficiency, subacute thyroiditis, congenital thyroid issues (T4→T3 conversion block, T4-R defic.) and neoplasm.
• Low voltage is seen due to pericardial myxedema, which insulates the heart and decreases voltage. Bradycardia is seen as a symptom of decreased circulating thyroid hormones.
• Low uptake of radioiodine is either due to general inflammatory damage of the follicular cells or some issue with the Na/I-symporter (“NIS”, upregulated by TSH, Wiki says there are sometimes anti-NIS Abs in thyroid disease).
• Initially, Hashimoto’s may present as hyperthyroidism as cells are destroyed and thyroid hormones are released, but always results in hypothyroidism as the gland loses function. (This is what Tunde and some document said… haven’t heard it elsewhere.)
• Note: Graves’ disease also starts as hyperthyroidism and progresses to late-stage hypothyroidism, so it would make sense to check anti-TSH-R Abs as well.

Question 49

4. A schoolgirl at the age of 14 without any complaints develops diffusely enlarged painless thyroid glands (this is a problem, she apparently has multiple thyroids) recognized accidentally by the school doctor. Laboratory findings: FT4 is slightly decreased , whereas total T3 is slightly elevated. Thyroid uptake of radioiodine is increased. FT4 gets normalized after treatment with inorganic iodine. What is the most likely diagnosis? Try to interpret the opposite changes in hormone levels.

Answer 49

• Enlarged, painless thyroid gland → goiter (see possible causes in answer to question 3)
• Since inorganic iodine normalizes T4 → iodine deficiency is the likely cause.
  
  • Endemic goiter is the term for this, in reference to the fact that it is often endemic in areas with soil (and thus food) of low iodine content. Iodine deficiency is rare in developed countries now, but may occur in pregnancy and puberty .
• Radioiodine uptake is increased. The Na-I symporter (NIS) is regulated in two ways, both of which may be at play here:
  
  1. Plasma iodide - an increase will downregulate NIS, a deficiency will upregulate it
  2. TSH - upregulates NIS transcription (TSH may be ↑ here due to low FT4)
• Because T4 incorporates 4 iodine atoms, whereas T3 incorporates only 3 and is more hormonally potent, T3 is preferentially synthesized in case of iodine deficiency .

Question 50

5. An 11 month old baby with protruded belly and retarded in movement development has been brought for medical evaluation. Serum FT4 and FT3 are decreased. Serum MIT/DIT are elevated and their urinary excretion increased. What is the most likely diagnosis?

Answer 50

• Cretinism - severely stunted mental/physical development due to congenital thyroid hormone deficiency.
• Cretinism can be due to “endemic” causes such as iodine deficiency, or genetic causes leading to enzyme or other protein deficiencies.
• Since MIT/DIT are elevated, but FT3/4 are decreased, this is likely a TPO deficiency resulting in an inability to sufficiently iodinate thyroid hormones. (Says Tunde, but I can’t read about this anywhere else.)
• Other genes/proteins altered in congenital hypothyroidism are TSH-R , TG , and iodotyrosine deiodinase.
• Perchlorate Test - Perchlorate is a competitive inhibitor of thyroid iodine uptake. First, administer radiolabeled iodine and perform scintigraphic measurement. Then administer perchlorate and re-measure scintigraphy. If TPO is functional, the “warmth” of the picture remains stable because much of the iodine has been oxidized and incorporated into hormones; if TPO is dysfunctional, perchlorate’s blocking of new iodine entry into the gland decreases the “warmth” of the image.

Question 51

6. List those thyroid tests that are considered helpful in the diagnosis of thyroid cancer!

Answer 51

• Imaging :
  
  • Ultrasound - can determine if a nodule is a fluid-filled cyst, solid or hollow
  • Scintigraphy - iodine-123 is administered and the gland is imaged using a gamma camera; can be used to cross-check functional status of nodes found via US
    
    • “cold nodes” - areas of low I uptake, indicate no hormone synthesis; if they are hollow, usually are cysts; if they are solid, often are malignancies
    • “warm nodes” - indicate I uptake and hormone synthesis; if solid on US and warm on scint., is probably an adenoma , usually benign
    • “hot nodes” - areas of such high synthetic activity that low TSH levels shut down the rest of the gland; may cause thyrotoxicosis (“toxic adenoma”)
  • Thyroglobulin - normally an intracellular protein, increase in plasma can indicate neoplasm or thyroiditis
  • Fine Needle Biopsy can be done on any growths detected via imaging and cytology can be performed to determine malignancy.
  • Ca⁺⁺ and Calcitonin - medullary carcinomas of the thyroid (from C cells) may secrete calcitonin and thus cause hypocalcemia . Calcitonin is thus a thyroid tumor marker.
  • CEA - also a tumor marker for medullary carcinoma
  • Palpation of nodules is a useful method during physical examination. Benign nodules tend to be soft, smooth and mobile; malignancies are more firm, irregular and fixed.
    
    • Age and gender are also factors in risk for malignancy. For example, thyroid growths in older females tend to be benign, while in younger males they tend to be malignant.

Question 52

1. Laboratory data of a patient with arterial hypertension include increased Na⁺ and decreased K⁺ concentrations. Urinary aldosterone excretion is twice normal. What is the most likely diagnosis if plasma renin activity is 1) high 2) low?

Answer 52

1. With high renin, some kind of kidney dysfunction or primary hypersecretion of renin is likely. There are two likely possibilities:
   
   • Renin-secreting tumor - these are rare, can perform imaging studies to check for this.
   • Low RBF (renal blood flow) - this could be due to blood or plasma loss, but the question mentions hypertension, so that is unlikely; external compression of the renal artery by a tumor or internal occlusion of the renal vessels by thrombosis/embolism are possible
   • CHD - Congestive heart failure
2. With low renin, some form of primary hyperaldosteronism (Conn’s syndrome) is present. This has two common causes:
   
   • Bilateral idiopathic adrenal hyperplasia - 66% of cases, usually due to a congenital adrenal enzyme defects
   • Adrenal adenoma - 33% of cases, can lead to hypertension, muscle issues and cardiovascular issues due to ion imbalances

Question 53

2. Plasma cortisol level of a patient is lower than normal. Urinary aldosterone excretion is decreased and the patient is hypoglycemic. What is the most likely diagnosis and what tests would you order?

Answer 53

• Deficiency of both cortisol and aldosterone indicate primary adrenal insufficiency which has several possible causes:
  
  • Autoimmune - Addison’s (often against 21-OHase), Autoimmune polyendocrine syndrome (affects multiple endocrine glands)
  • Infection - as in meningococcal Waterhouse-Friderichsen syndrome , tuberculosis (adrenal insuffic. is often 1st sign of TB), pseudomonas, fungi or viruses
  • Congenital Adrenal Hyperplasia - usually via 21-OHase genetic defect
• If the onset was rapid, or any other signs such as petechial rash are present, suspect meningococcal infection.
  
  • CSF microscopy to check for presence of gram negative diplococci either in the fluid or in WBCs; PCR can also be used if available
• If onset was slower, suspect Addison’s disease.
  
  • ACTH stimulation test - uses synthetic ACTH “tetracosactide”; short (small dose, test cortisol 1 hr later) and long (large dose, test cortisol 4 times over 1 day) versions are done; if appropriate cortisol response is seen, Addison’s can be ruled out
  • Other signs of Addison’s are ↑ Ca ++ / ↓ Na + / ↑ K + / metabolic acidosis / ↑ WBCs (but none of these are specific)
  • Skin bronzing is another sign of Addison’s. Can check the gums/oral mucosa for bronzing in places with no sun exposure.
  • If Addison’s is present, hormone therapy is needed
• Note: the hypoglycemia is due to loss of cortisol’s gluconeogenic effects.

Question 54

3. A 24-year-old man complains of gradually increasing weakness, weight loss and loss of appetite. He was observed to have bronzed skin, however, he reported no exposure to the sun. He was hypotensive and showed evidence of muscle wasting. The results of the laboratory test included: serum Na⁺ 125 mmol/l, serum K⁺ 6.2 mmol/l, plasma cortisol: 4 μg/dl (8:00 a.m.) (decreased), plasma ACTH: increased above normal. An ACTH stimulation test failed to elicit response in plasma cortisol level. What is the most likely diagnosis?

Answer 54

• Hyponatremia (<135 mM) and hyperkalemia (>5 mM) indicate low aldosterone.
• Seeing both low aldosterone and low cortisol indicate primary adrenal insufficiency. (Secondary tends to present with only low cortisol, unless ACTH deficiency is prolonged.)
• Gradual onset rules out meningococcal infection, or other acute infectious causes. (Although, acute onset can occur in patients with mild adrenal insufficiency under stress.)
• Weakness/muscle wasting, weight/appetite loss, bronzed skin (preprohormone of ACTH = POMC which includes MSH peptide; with ↑ ACTH comes ↑ MSH → bronzing) and hypotension are all clinical signs of adrenal insufficiency (either primary or secondary).
• Increased ACTH and an ACTH test failing to elicit response → Addison’s disease.
• Treatment is cortisol and aldosterone supplementation.

Question 55

4. A patient with Cushing’s syndrome entered the hospital for diagnostic studies. Baseline plasma cortisol was elevated. A small dose of dexamethasone did not suppress cortisol but 50% reduction occurred when large dose of dexamethasone was given. Plasma ACTH was elevated . What is the most likely diagnosis?

Answer 55

• Cushing’s syndrome is a collection of signs/symptoms related to excess cortisol exposure.
  
  • It is either due to excess exogenous corticosteroid (i.e. prednisone) or a corticosteroid or ACTH-secreting tumor. These tumors can be within the pituitary/adrenal gland or ectopic.
• Cushing’s disease is a cause of Cushing’s syndrome involving increased ACTH secretion usually either via pituitary adenoma or elevated hypothalamic CRH secretion. It does not include ectopic (non-pituitary) ACTH secretion.
• Dexamethasone is a synthetic corticosteroid that provides negative feedback on the pituitary in order to decrease ACTH secretion.
• Dexamethasone Suppression Test - uses both low (2 mg) and high (8 mg) doses to determine presence and cause of Cushing’s syndrome after a 24-hr urinary free cortisol test determines elevated cortisol
  
  • Low-Dose (2 mg) - if cortisol is suppressed, no endogenous cortisol hypersecretion exists (i.e. no Cushing’s syndrome); if it is not suppressed, some form of Cushing’s syndrome exists → ACTH levels must be checked and then high dose test is performed to determine the cause.
  • High-Dose (8 mg) - several possible reactions exist:
    
    • Low ACTH / No Cortisol Suppression - ACTH-independent Cushing’s syndrome
      
      • AKA “adrenal Cushing’s”, either adrenal hyperplasia or neoplasm is likely
      • perform adrenal CT and adrenalectomy if necessary
    • Normal or High ACTH / No Suppression - ectopic ACTH syndrome
      
      • often via a small cell carcinoma of lung
      • perform chest/abdominal CT and surgical removal of ectopic source
    • Normal or High ACTH / Suppression - pituitary Cushing’s disease
      
      • an ACTH-secreting pituitary adenoma is likely
      • pituitary adenoma = most common cause of Cushing’s syndrome (90%)
      • perform pituitary MRI and hypophysectomy if necessary
    • If the high-dose result is unclear, a CRH-stimulation test can be done via administration of IV CRH, and inferior petrosal sinus sampling is done to determine the source of elevated ACTH.
      
      • If CRH raises petrosal sinus ACTH levels → pituitary Cushing’s disease
      • If CRH does not raise ACTH levels → ectopic ACTH
      • In this case, since ACTH levels were high, and high dose dexa suppressed cortisol levels, the patient most likely has Cushing’s disease involving a pituitary adenoma.
      • A pituitary MRI should be performed.

Question 56

5. A hypertensive male patient enters the hospital for medical evaluation. His blood pressure is 180/95 mmHg ; Serum Na⁺: 148 mmol/l, K⁺: 3.5 mmol/l, fasting plasma glucose: 7.2 mmol/l. Baseline plasma cortisol was elevated. A small dose of dexamethasone did not suppress cortisol. A large dose of dexamethasone was given but there was little change in the blood cortisol from baseline values. Plasma ACTH was high. What is the most likely diagnosis?

Answer 56

• Since ACTH was high and both low/high dose dexa tests produced no change, this is ectopic ACTH syndrome
• Hypertension, hypernatremia and hypokalemia (K⁺ actually at low end of normal in this case) can be explained by the fact that cortisol has mineralocorticoid activity and thus may produce similar effects to hyperaldosteronism. This effect is especially common in ectopic ACTH syndrome.
• Glucose is elevated due to cortisol’s gluconeogenic effects.
• A chest/abdomen CT should be performed and any ectopic ACTH source removed.

Question 57

6. A 40-year-old woman complains of amenorrhea and emotional disturbances , perhaps partially due to her increasing obesity which is concentrated around the chest and the abdomen . Her X-ray studies show evidence of mineral bone loss ( osteoporosis ). Laboratory results: serum K+ 3.2 mmol/l, fasting plasma glucose: 7.7 mmol/l, plasma cortisol: 40 μg/dl (8:00 a.m.) (elevated), plasma ACTH is lower than normal. A large dose of dexamethasone did not suppress the elevated cortisol level.

What is the most likely diagnosis?

Answer 57

• Since ACTH was low and both doses of dexa produced no results, this is an ACTH-independent form of Cushing’s syndrome either due to adrenal hyperplasia or adrenal neoplasm.
• Cortisol excess can cause amenorrhea and male-like weight gain patterns in women.
• Excess cortisol can lead to bone demineralization → osteoporosis
• Hyperglycemia is due to cortisol’s gluconeogenic effects.
• Low K⁺ may be either due to mineralocorticoid secretion by the neoplastic/hyperplastic adrenal or mineralocorticoid activity of cortisol.
  
  • Adrenal carcinomas tend to secrete multiple adrenocortical hormones*, whereas *benign adenomas usually secrete only one type. Both types tend to secrete hormones randomly and autonomously, without regulation from the HPA axis.
• Abdominal CT/MRI can be used to check for an adrenal mass; adrenalectomy can be performed if one is found.

Question 58

7. A young girl develops virilization and hypertension . Plasma cortisol is low, ACTH is elevated.

What is the most likely cause of this condition?

How are adrenal production of glucocorticoids, mineralocorticoids and androgens affected?

Answer 58

• Virilization with low cortisol suggests adrenogenital syndrome, a form of congenital adrenal hyperplasia (CAH).
• This is most commonly due to an autosomal recessive 21-OHase deficiency, leading decreased mineralocorticoid/glucocorticoid and increased androgen production.
  
  • Excess androgens cause virilization, hirsutism, infertility and premature adrenarche.
  • Lack of aldosterone leads to hyperkalemia and hypotension.
  • (Since this patient is hyper- rather than hypotensive, this is a different enzyme deficiency.)
• Lack of 11β-hydroxylase, another autosomal recessive disorder, is a much more rare form of CAH (only 5%).
  
  • Androgen excess causes the same symptoms as in 21-OHase deficiency.
  • 11-Deoxycorticosterone (DOC) , an aldosterone precursor with mineralocorticoid activity, accumulates and can lead to hypertension and hypokalemia.
• Since this patient was hypertensive it is most likely the rarer 11β-hydroxylase form of adrenogenital syndrome.
• Treatment is cortisol supplementation to suppress ACTH and thus androgen/MC excess (as well as replacing the lacking cortisol).

Question 59

8. A young boy develops precocious puberty and arterial hypotension. Plasma ACTH is elevated, serum Na⁺ is low. The deficiency of which enzyme is presumably responsible for the the above findings? Urinary excretion of 17-ketosteroids, DHEA and free cortisol are probably normal, low or elevated?

Answer 59

• This is CAH due to a lack of 21-hydroxylase , the more common form (1:10,000) sometimes known as the “salt-losing” or classical form.
• Hypotension and low Na⁺ indicate lack of mineralocorticoid activity.
• Precocious puberty indicates androgen excess.
• Urinary 17-ketosteroids and DHEA would be high due to androgen overproduction.
• Free cortisol would be low due to lack of a necessary cortisol synthesis enzyme.

Question 60

9. A 40-year-old man complains of spells of headache , profuse perspiration (diaphoresis), nausea and palpitations. Arterial blood pressure is markedly elevated . Urinary VMA excretion is increased.

What is the most likely diagnosis?

What test would you order to confirm your diagnosis?

Answer 60

• This is probably pheochromocytoma, a norepinephrine-secreting tumor formed by chromaffin cells of the adrenal medulla.
  
  • Sometimes known as “10% tumors” because ~10% of them are bilateral, extra-adrenal, familial or malignant.
  • Extra-adrenal PCC-like tumors are called “paragangliomas”.
• All symptoms can be explained by increased adrenergic receptor stimulation.
• Vanillylmandelic acid (VMA) is a breakdown product of catecholamines.
• Tests:
  
  • Urinary Homovanillic acid (HVA) can be tested to see if there is any dopaminergic excess involved.
  • Serum Chromogranin A can be tested. It is a peptide related to neuroendocrine secretion and elevated in pheochromocytoma.
  • Clonidine Suppression Test - clonidine is an adrenergic agonist which will normally decrease circulating catecholamines; in case of pheochromocytoma, no decrease is seen; requires careful monitoring and is not often used anymore
  • Imaging - ultrasound, MRI or CT of the adrenal gland
    
    • 131 I-MIBG - a radiolabeled, adrenal-specific agent that can be injected to visualize the adrenal gland and any tumors that may be present within it