Abdo stuff

Question 1

What is the pathophysiology of NAFLD?

Answer 1

Pathophysiology includes fat accumulation (steatosis), inflammation, and, variably, fibrosis. Steatosis results from hepatic triglyceride accumulation. Possible mechanisms for steatosis include reduced synthesis of very low density lipoprotein (VLDL) and increased hepatic triglyceride synthesis (possibly due to decreased oxidation of fatty acids or increased free fatty acids being delivered to the liver). Inflammation may result from peroxidative damage to cell membranes. These changes can stimulate hepatic stellate cells, resulting in fibrosis. If advanced, NASH can cause cirrhosis and portal hypertension.

Question 2

What are the clinical manifestations of NAFLD?

Answer 2

SYMPTOMS:
-The majority of patients with steatosis have no symptoms.
-Patients with steatohepatitis may report persistent fatigue, malaise or right upper quadrant pain
-Advanced disease may present with symptoms of cirrhosis such as ascites, oedema and jaundice

SIGNS:
-Presentation is often coincidental from routine medicals and blood tests revealing abnormal LFTS (eg Raised alanine transferase)
-Hepatomegaly (75% of patients), splenomegaly may develop if there is advanced hepatic fibrosis and is usually the first indication that portal hypertension has developed.
-Signs of chronic liver disease may be seen in patients with cirrhosis (ascites, oedema, spider naevi), although patients with cirrhosis due to NASH can also be asymptomatic and lack the usual signs of chronic liver disease

Question 3

How is NAFLD investigated?

Answer 3

FIRST LINE:
1. Take an alcohol history to rule out alcohol-related liver disease
2. Examination: Hepatomegaly is very common. Splenomegaly with or without portal hypertension may occur with cirrhosis.
3. Bloods: LFTs may show mildly raised ALT relative to AST but this tends to reverse if the disease progresses and then the ALT falls (up to 50% of patients can have normal ALT and AST levels.) Other blood tests are used for distinguishing from associated causes: Fasting lipids (usually raised), fasting glucose, FBC, Viral studies (hepatitis), Iron studies, Caeruloplasmin, Autoimmune studies (ANA, ASMA may be raised in NASH)

GOLD STANDARD/ DIAGNOSTIC:
-Rule out other causes of liver disease and check for associated metabolic disorders (obesity, dysplipidaemia, diabetes, hypertension)
-Liver biopsy: only definitive test. Is performed to confirm diagnosis, exclude other causes, assess extent and predict prognosis. Severity can be scored.
-Diagnostic imaging: US has some diagnostic accuracy in detecting steatosis, but is not good at distinguishing NASH and fibrosis within NAFLD. CT scanning can help to monitor the course of disease. MRI scan can also be used to exclude fatty infiltration and the course and extent of disease.

Question 4

How is NAFLD managed?

Answer 4

FIRST-LINE
Control risk factors including obesity (bariatric surgery helps). The mainstay of management is weight loss where appropriate and control of comorbidity (BP, DM, lipids). Address cardiovascular risk (commonest cause of death). Avoid alcohol consumption. No drug is of proven benefit, though Vitamin E may improve histology in fibrosis
-Diet: gradual weight loss is important. Diets should have a high protein: calorie ratio, a typical low-fat-diabetes-type diet is recommended, abstinence from alcohol is recommended for all types of steatosis and steatohepatitis.
-Exercise: exercise with diet increases muscle mass and increases insulin sensitivity. Improving cardiovascular fitness and weight training should improve NASH.
-Surgery: Bariatric surgery can bring about histological and biochemical improvements in NASH.
-In secondary or tertiary care settings only, consider pioglitazone or vitamin E for adults with advanced liver fibrosis, whether they have diabetes or not.

REFERRAL
-May be needed to a hepatologist for staging and prognosis
-May be necessary to exclude alcohol-related liver disease, haemochromatosis, autoimmune hepatitis or where there is doubt over the diagnosis or the cause
-To a gastroenterologist, or hepatologist when there are complications such as cirrhosis or liver failure, is mandatory.

FOLLOW-UP
Monitor for complications (NASH, Cirrhosis, DM). If Cirrhotic, screen for HCC with ultrasound +/- AFP twice-yearly.
It may be possible to prevent steatohepatitis by actively screening for patients at risk of steatosis and educating them about diet, exercise and alcohol.

Question 5

What is the prognosis of NAFLD?

Answer 5

Steatohepatitis can progress to cirrhosis and liver failure just like any chronic liver disease. Poor control of hyperlipidaemia or diabetes will also accelerate progression of fibrosis. Liver cancer can occur at the same rate as with other forms of liver disease. The prognosis depends on the stage of disease

Steatosis: good prognosis with abstinence and gradual weight loss. Cirrhosis develops in 1-2% over 20 years. Central obesity and insulin resistance are risk factors for diabetes mellitus and for cardiovascular and renal disease

Steatohepatitis: 10-12% will progress to cirrhosis within 8 years. This is similar to the rate of progression towards cirrhosis in alcohol-related liver disease

Question 6

What are steatosis/steatohepatitis?

Answer 6

Steatosis (fatty liver) is an accumulation of fat in the liver. When this progresses to become associated with inflammation, it is known as steatohepatitis.

Question 7

What is the pathophysiology of alcoholic liver disease?

Answer 7

Fatty liver (steatosis) involves the accumulation of triglycerides and other lipids in hepatocyte. This is a result of defective fatty acid metabolism, which may be caused by imbalance between energy intake and combustion, by mitochondrial damage (alcohol), by insulin resistance, or by impairment of receptors and enzymes involved.
Alcohol is readily absorbed from the stomach, but most is absorbed from the small intestine. Alcohol cannot be stored. A small amount is degraded in transit through the gastric mucosa, but most is catabolised in the liver, primarily by alcohol dehydrogenase (ADH). There is inhibition of fatty acid oxidation and gluconeogenesis, promoting fat accumulation in the liver.
There is also oxidative damage due to liver hypermetabolism, reduction in protective antioxidants (caused by alcohol-related undernutrition), accumulation of neutrophils. There is worsening inflammation, cell necrosis and apoptosis result in hepatocyte loss and subsequent attempts at regeneration result in fibrosis.

Question 8

What are the clinical features of alcoholic liver disease?

Answer 8

SYMPTOMS:
Presentation is often coincidental from routine medicals and blood tests revealing abnormal LFTs (eg raised alanine transaminase)
-Malaise
-Anorexia
-Diarrhoea, Vomiting
-Bleeding
-Ascites

SIGNS:
-Increased TPR
-Tender hepatomegaly (common) +/- jaundice
-Jaundice, encephalopathy or coagulopathy indicate severe hepatitis
-Splenomegaly with or without portal hypertension may occur with cirrhosis
-Signs of chronic liver disease may be seen in patients with cirrhosis (ascites, oedema, spider naevi)

1. Fatty liver: Acute/reversible, but may progress to cirrhosis if drinking continues. The majority of patients with steatosis have no symptoms. Enlarged liver.
2. Alcoholic hepatitis: 80% progress to cirrhosis (hepatic failure in 10%). On direct questioning many patients with steatohepatitis report persistent fatigue, malaise or right upper quadrant pain.
3. Cirrhosis: Irreversible liver damage. Presents with ascites, oedema and jaundice. May be portal hypertension (often with oesophageal varices)

Question 9

How is alcoholic liver disease investigated?

Answer 9

FIRST LINE:
-History: harmful or hazardous drinking
-Bloods: Increased WCC, decreased platelets (toxic effect or hypersplenism), increased INR, AST, MCV, Urea. LFTS: mildly raised ALT is often the first change relative to AST but this tends to reverse if disease progresses, and then ALT falls. Up to 50% of patients can have normal ALT and AST levels. When alcohol is the cause there is raised Gamma-GT.
-Other blood tests are used for distinguishing from associated causes: Fasting lipids (usually raised), fasting glucose, FBC, Viral studies (hepatitis), Iron studies, Caeruloplasmin, Autoimmune studies (ANA, ASMA may be raised in NASH)

GOLD STANDARD/ DIAGNOSTIC:
A definitive diagnosis can only be achieved by liver biopsy and histopathological analysis. Biopsy is performed to confirm diagnosis, exclude other causes, assess extent and predict prognosis. Severity can be scored. In Cirrhosis you see Mallory bodies +/- neutrophil infiltrate (can be indistinguishable from NASH)
-Diagnostic imaging: may be used to define extent and course of disease. Steatohepatitis is usually diffuse, whereas steatosis may be focal or diffuse. US good for detecting steatosis but not good at distinguishing NASH and fibrosis within NAFLD. CT scanning may be helpful to monitor the course of the disease. MRI can exclude fatty infiltration.

Question 10

How is alcoholic fatty liver disease managed?

Answer 10

Treating alcohol-related fatty liver
Managed by abstinence and adequate diet. Abstinence can reverse alcohol-related steatosis.
-Chlordiazepoxide can be given for alcohol withdrawal
-Vitamins may be needed

Treating alcoholic hepatitis
-Most need hospitalising, urinary catheter and CVP monitoring may be needed
-Screen for infections +/- ascitic fluid tap and treat for SBP (must be considered in any patient with ascites who deteriorates suddenly, treat with piperacillin with tazobactam, give prophylaxis to high risk patients or those who have had a previous episode)
-Stop alcohol consumption: for withdrawal symptoms, if chlordiazepoxide by the oral route is impossible, try IM lorazepam
-Vitamins: Vitamin K, Thiamine,
-Optimise nutrition (35-40kcal/kg/day non-protein energy). Use ideal body weight for calculations eg if malnourished. Don’t use low protein diets even if severe encephalopathy is present
-Monitor daily weight, LFT, U&E, INR. Hyponatraemia is common but water restriction may make matters worse.
-Steroids: may confer benefit in those with severe disease, prednisolone (contraindications: sepsis, variceal bleeding). Should only be given only after effectively treating any active infection or GI bleeding and controlling any renal impairment.

Transplantation
Refer patients with decompensated liver disease (liver disease complicated by jaundice, ascites, variceal bleeding or hepatic encephalopathy) to be considered for assessment for liver transplantation if they:
-Still have decompensated liver disease after best management and 3 months’ abstinence from alcohol
-Are otherwise suitable candidates for liver transplantation

Question 11

What is the pathophysiology of cirrhosis?

Answer 11

Cirrhosis is a diffuse hepatic process in response to hepatocyte damage characterised by bridging fibrosis and the conversion of normal liver architecture into structurally abnormal nodules of regenerating cells. It represents the final histological pathway for a wide variety of liver diseases.

The progression to cirrhosis is very variable and may occur over weeks or many years. The fibrosis causes distortion of the hepatic vasculature and can lead to an increased intrahepatic resistance and portal hypertension. Portal hypertension can lead to oesophageal varices as well as hypoperfusion of the kidneys, water and salt retention and increased cardiac output. Damage to liver cells (hepatocytes) causes impaired liver function and the liver becomes less able to synthesise important substances such as clotting factors and is also less able to detoxify other substances.

Question 12

What are the clinical manifestations of cirrhosis?

Answer 12

SYMPTOMS:
Often asymptomatic until there are obvious complications of liver disease
-May present with vague symptoms such as fatigue, malaise, anorexia, nausea and weight loss.
Advanced decompensated liver disease:
-Oedema
-Ascites
-Easy bruising
-Poor concentration and memory
-Spontaneous bacterial peritonitis

SIGNS:
Variable and depend upon extent of disease.
1. Cutaneous features: Jaundice, scratch marks secondary to pruritus, spider naevi, palmar erythema, bruising, petechiae or purpura, hair loss, leukonychia (white nails), finger clubbing
2. Other: hepatomegaly and nodular liver, oedema, gynaecomastia and male hair loss pattern, hypogonadism/ testicular atrophy/ amenorrhoea (due to the direct toxic effect of alcohol in alcoholic cirrhosis or iron in haemochromatosis), parotid enlargement.
3. Signs of portal hypertension: ascites, caput medusae, splenomegaly, oesophageal varices.
4. Signs of hepatic encephalopathy: asterixis (flapping tremor)

Question 13

How is cirrhosis investiated?

Answer 13

-Thorough history for possible underlying causes of cirrhosis, including full drug history and alcohol history, risk factors for hepatitis and family history of autoimmune disease
-LFTs: AST, ALT, Alk-Phos, bilirubin, gamma-GT. AST and ALT are raised due to hepatocyte damage; gamma-GT is high in active alcoholics
-Albumin: hypoalbuminaemia in advanced cirrhosis
-FBC: anaemia from bleeding, thrombocytopenia from hypersplenism, macrocytosis from alcohol abuse
-Coagulation screen: PTT reduced in advanced cirrhosis
-Viral antibody screen: for Hep B/C
-Fasting glucose/insulin/triglycerides and uric acid levels if NASH is suspected
-Alpha-1 antitrypsin: deficiency
-Caeruloplasmin and urinary copper: Wilson’s disease

GOLD STANDARD/ DIAGNOSTIC:
-Transient elastography or acoustic radiation force impulse imaging: to diagnose cirrhosis for people with NAFLD and advanced liver fibrosis
-Liver biopsy: to diagnose cirrhosis when transient elastography is not suitable. If there are clear signs of cirrhosis (ascites, coagulopathy, shrunken nodular liver) confirmation of diagnosis by biopsy may not be necessary

OTHERS:
-USS of liver and possibly CT or MRI: mainly used to detect complications of cirrhosis such as splenomegaly, ascites or hepatocellular carcinoma. Caudate lobe may be enlarged.
-CXR: may show an elevated diaphragm and even pleural effusion (due to passage of ascitic fluid across the diaphragm)
-Ascitic tap to look for neutrophils indicative of peritonitis.

Question 14

How is cirrhosis managed?

Answer 14

Aim of treatment is to delay progression of cirrhosis and to prevent and/or treat any complications.
-Specific treatment for the underlying cause
-Ensure adequate nutrition, including calorie and protein intake
-Stop drinking alcohol
-Fluid management (diuretics)
-Zinc supplements for those with deficiency
-Antihistamines and topical ammonium lactate for mild itching, cholestyramine for pruritus. Rifampicin if unresponsive to pruritus
-Preventative treatment for osteoporosis
-Regular exercise to prevent muscle wasting
-Prophylactic antibiotics to reduce bacterial infections.
-Vaccination against hepatitis A, influenza and pneumococci
-Drug prescribing: avoid drugs that may not be properly metabolised in the presence of liver failure, have an adverse effect on the degree of liver failure or be a cause of drug-induced liver disease.
-Liver transplantation is the ultimate treatment for cirrhosis and end-stage liver disease

Question 15

What are the complications of cirrhosis?

Answer 15

1. Anaemia, thrombocytopenia and coagulopathy: anaemia may result from folate deficiency, haemolysis or hypersplenism. Thrombocytopenia is usually secondary to hypersplenism and decreased levels of thrombopoietin. Coagulopathy results from decreased hepatic production of coagulation factors. May also be fibrinolysis and DIC.
2. Oesophageal varices: can occur as a result of portal hypertension. Those with upper GI bleeding should be given prophylactic IV antibiotics at presentation.
3. Ascites: common feature of cirrhosis.
4. Spontaneous bacterial peritonitis: may be associated with ascites. Thought to be caused by the spread of bacteria across the gut wall and/or haematogenous bacterial spread. E coli is the most common. May be prevented by adequately treating ascites. After an episode, patients should be given long-term prophylaxis with oral antibiotics: norfloxacin, levofloxacin or trimethoprim.
5. Hepatocellular carcinoma: risk varies according to cause of cirrhosis. Most often associated with Hep C. Lower risk in alcoholic cirrhosis or primary biliary cirrhosis

Question 16

What is ascites and what are the causes?

Answer 16

Ascites is the excessive accumulation of fluid in the abdominal cavity. Ascites that is not infected and not associated with hepatorenal syndrome may be graded:
Grade 1: mild ascites, only detectable by USS
Grade 2: moderate ascites causing moderate symmetrical distension of the abdomen
Grade 3: large ascites causing marked abdominal distension
Refractory ascites can be divided into 2 groups:
1. Diuretic-resistant ascites: refractory to sodium restriction and intensive diuretic treatment for at least one week
2. Diuretic-intractable ascites: refractory to therapy due to the development of diuretic-induced complications that preclude the use of an effective dose of diuretic

CAUSES: Liver cirrhosis is the commonest cause: peripheral arterial vasodilation (mediated by nitric oxide and other vasodilators) leads to a reduction of effective blood volume, with activation of the sympathetic nervous system and RAAS, promoting water and salt retention.
Ascites can be transudative (cirrhosis, portal hypertension, hepatic outflow obstruction, Budd-Chiari syndrome, cardiac failure etc) or exudative (pancreatitis, nephrotic syndrome, peritoneal carcinomatosis, peritoneal tuberculosis etc).

Question 17

What are the presenting features of cirrhosis?

Answer 17

PRESENTATION
Swelling and fullness of the abdomen, particularly the flanks. Symptoms may include increased abdominal size, increased weight, abdominal discomfort and shortness of breath. There may be nausea and vomiting.
Tense ascites is uncomfortable and produces respiratory distress. Pleural effusion (usually right sided) and peripheral oedema may be present.

There is usually shifting dullness to percussion of the abdomen on examination.

Question 18

How is ascites investigated?

Answer 18

A diagnostic aspiration of 10.20ml of ascitic fluid should be carried out in all patients, and the following performed:
- Albumin: an ascitic albumin conc of >11g/l below the serum albumin suggests transudate; a value of <11g/l suggests an exudate
- Neutrophil count: >250cells/mm3 in cirrhotic ascites indicates underlying (usually spontaneous) bacterial peritonitis
- Gram stain and culture (MC&S) for bacteria and acid fast bacilli
- Cytology for malignant cells
- Amylase to exclude pancreatic ascites

Question 19

How is ascites managed?

Answer 19

MANAGEMENT
- Fluid restriction (<1.5L/day), restrict salt intake
- Give spironolactone and increase dose as tolerated
- Chart daily weight and aim for fluid loss of <500g/day
- If spironolactone ineffective, give furosemide (must monitor Na+ closely)
- Therapeutic paracentesis with concomitant albumin infusion may be required
- Transjugular intrahepatic portosystemic shunt (TIPS) is occasionally used for resistant ascites.

Question 20

What are the complications of cirrhosis?

Answer 20

COMPLICATIONS
Spontaneous bacterial peritonitis (SBP) occurs in 8% of cirrhotic patients with ascites and has a mortality rate of 10-15% (E. coli is the most common infective organism).
Pleural effusion is another potentially serious complication.

Question 21

What is portal hypertension and what are the causes?

Answer 21

Refers to an abnormally high pressure in the hepatic portal vein. Clinically significant portal hypertension is defined as an hepatic venous pressure gradient of 10 mm Hg or more

AETIOLOGY
Cirrhosis is the most common cause
1. Prehepatic: portal vein thrombosis, portal vein obstruction (congenital atresia/ stenosis), splenic vein thrombosis, extrinsic compression eg tumour
2. Intrahepatic: Cirrhosis, chronic hepatitis, schistosomiasis, myeloproliferative diseases, idiopathic portal hypertension, granulomata eg sarcoid, nodular, toxins, fibropolycystic disease
3. Posthepatic: compression (eg from tumour), Budd-Chiari syndrome, constrictive pericarditis (and rarely right-sided heart failure)
4. Other: increased hepatic blood flow (increased splenic blood flow eg splenomegaly, hepatoportal AV fistula), idiopathic

PATHOPHYSIOLOGY
Develops due to increased vascular resistance in the portal venous system (liver damage activates stellate cells and myofibroblasts) and increased blood flow in the portal veins (from splanchnic arteriolar vasodilation). The raised pressure opens up venous collaterals, connecting the portal and systemic venous systems. Portosystemic venous anastamoses can cause encephalopathy, possibly due to various toxins bypassing the liver’s detoxification process. Portal hypertension leads to salt and water retention, ascites and hyponatraemia.

Question 22

What are the presenting features of portal hypertension?

Answer 22

PRESENTATION
Signs: dilated veins in the anterior abdominal wall and caput medusae, venous hum over large upper abdominal collaterals, splenomegaly, ascites
Signs of liver failure: jaundice, spider naevi, palmar erythema, signs of encephalopathy (confusion, liver flap, fetor hepaticus), signs of hyperdynamic circulation (bounding pulse, low BP, warm peripheries), enlarged or small liver, gynaecomastia and testicular atrophy

Question 23

How is portal hypertension investigated?

Answer 23

INVESTIGATIONS
-History: for causes of liver disease (jaundice, alcohol, infection, FH) and complications of portal hypertension (Varices, encephalopathy, ascites, SBP)
-Bloods: LFTs, U&Es, FBC, Clotting
-Scans: Abdominal USS, doppler ultrasound, spiral CT, MRI scan
-Endoscopy: for oesophageal varices
-Portal hypertension measurement: hepatic venous pressure gradient (HVPG)
-Liver biopsy: if indicated
-Vascular imaging

Question 24

How is portal hypertension managed?

Answer 24

MANAGEMENT
-Treat the underlying cause
-Liver transplantation
-Beta-blockers +/- nitrates
-Shunt procedures (TIPS): connecting the portal and hepatic veins using a shunt
-Conservative management includes salt restriction and diuretics

Question 25

What are the complications of portal hypertension?

Answer 25

COMPLICATIONS:
-Bleeding from varices
-Ascites and its complications (SBP, hepatorenal syndrome)
-Pulmonary complications
-Liver failure
-Hepatic encephalopathy
-Cirrhotic cardiomyopathy

Question 26

What are varices?

Answer 26

Variceal haemorrhage occurs from dilated veins (varices) at the junction between the portal and systemic venous systems. Varices tend to be in the distal oesophagus and/or the proximal stomach but isolated varices may be found in the distal stomach, large and small intestine. Bleeding is characteristically severe and may be life threatening. The size of the varices and their tendency to bleed are directly related to the portal pressure, which is usually directly related to the severity of underlying liver disease. Large varices with red spots are at highest risk of rupture

Question 27

What are the causes of varices?

Answer 27

AETIOLOGY
The causes of oesophageal varices are anything that can cause portal hypertension:
1. Prehepatic: portal vein thrombosis, portal vein obstruction (congenital atresia/ stenosis), increased portal flow (fistula), increased splenic flow
2. Intrahepatic Cirrhosis due to various causes, including alcoholic hepatitis and chronic hepatitis (eg viral or autoimmune), idiopathic portal hypertension (hepatoportal sclerosis), acute hepatitis (especially alcoholic), schistosomiasis, congenital hepatic fibrosis, myelosclerosis
3. Posthepatic: compression (eg from tumour), Budd-Chiari syndrome, constrictive pericarditis (and rarely right-sided heart failure)

RISK FACTORS FOR VARICEAL BLEEDING
Risk factors are the same as those that increase the risk of portal hypertension: decompensation of liver disease, malnourishment, alcohol intake, physical exercise, circadian rhythms, increased intra-abdominal pressure, Aspirin, NSAIDs, bacterial infection

Question 28

What are the presenting features of varices?

Answer 28

PRESENTATION
Symptoms: haematemesis (most commonly), abdominal pain, features of liver disease and specific underlying condition, dysphagia/ odynophagia, confusion secondary to encephalopathy
Signs: peripherally shut down, pallor, hypotension and tachycardia (ie shock), reduced urine output, melaena, signs of chronic liver disease, reduced GCS, signs of sepsis.

Question 29

How are varices investigated?

Answer 29

INVESTIGATIONS
-Endoscopy is required at an early stage: emergency fibre-optic endoscopy confirms the diagnosis and source of bleeding
-Bloods: FBC (Hb may be low, MCV may be high, normal or low, platelets may be low, WCC may be raised), clotting including INR, Renal function, LFTs, group and cross-match
-CXR: patients may have aspirated or have a chest infection
-Ascitic tap: if bacterial peritonitis is suspected

Question 30

How are varices managed?

Answer 30

MANAGEMENT
-Vasoactive drugs: Terlipressin, treatment should be stopped after definitive haemostasis has been achieved, or after 5 days.
-Endoscopic band ligation
-Prophylactic antibiotics: significantly reduces mortality
-Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for those who do not respond or are unlikely to respond to standard initial management eg if bleeding is not controlled by band ligation. Hepatic vein is cannulated percutaneously via the internal jugular vein and a tract is created through the liver from hepatic to portal bein, reducing portal pressure
-Endoscopic injection of N-butyl-2-cyanoacrylate (a glue like substance which embolises varices) should be offered to patients with UGIB from gastric varices
-Resuscitation: assess airway, wide-bore access, provide oxygen, fluid resuscitation with rapid infusion of crystalloid and colloid solution, give blood (cross-matched) as soon as possible , NG tube, correct anaemia and coagulopathy

Question 31

What is the aetiology and pathophysiology of biliary tract disease?

Answer 31

AETIOLOGY
Bile contains cholesterol, bile pigments (from broken down Hb) and phospholipids. If the concentrations vary different stones may form:
1. Pigment stones: small, friable and irregular, caused by haemolysis (eg sickle cell anaemia, thalassemia, cirrhosis)
2. Cholesterol stones (80% in UK): large, often solitary, radiolucent.. Causes are being female, fat and old.
3. Mixed stones: faceted (calcium salts, pigment and cholesterol), 10% are radiopaque
4. Brown pigment stones: form as a result of stasis and infection within the biliary system, usually in the presence of E. coli and Klebsiella

PATHOPHYSIOLOGY
Gallstones: Cholelithiasis occurs when the physical characteristics of bile alter so that cholesterol is less soluble or there is an excess of bile pigments. Diminished contractility of the gallbladder may also be a contributory factor leading to biliary stasis. May exist for many years without causing symptoms however they may also cause severe pain (biliary colic) or they may pass into the common bile duct and cause obstructive jaundice or cholangitis.

Acute cholecystitis: caused by distention of the gallbladder (due to impaction of a stone in the cystic duct) with subsequent necrosis and mucosal wall ischaemia.

Question 32

What are the different clinical manifestations of biliary tract disease?

Answer 32

Up to 70% of patients with gallstones are asymptomatic at time of diagnosis

Biliary colic: Right upper quadrant pain (sudden onset) which radiates to the back in interscapular region) with or without jaundice. Nausea or vomiting (as a result of distention of the gallbladder)

Acute cholecystitis: right upper quadrant or epigastric pain which is referred to the right shoulder. Vomiting, fever, localised peritonism or a GB mass. Main difference with biliary colic is the inflammatory component.
Murphy’s sign: pain on inspiration when two fingers are lay on RUQ. Pain absent when repeated on LUQ.

Ascending cholangitis: form Charcot’s triad - Intermittent fever usually with rigors, abdominal pain (right upper quadrant), intermittent jaundice. Can be hypotension due to septic shock and confusion. There may also be acholic stools and pruritus. Commonly Klebsiella and E. coli. Also common after ERCP.

Question 33

How is biliary tract disease investigated?

Answer 33

GALLSTONES:
-Usually diagnosed by US, those containing calcium may be seen on plain Xray

BILIARY COLIC
-Urinalysis, ECG, CXR to help exclude other diseases
-LFTs, pancreatic enzymes

ACUTE CHOLECYSTITIS:
-FBC: Increased WCC
-Thick walled shrunken gallbladder on US, pericholecystic fluid, stones and dilated CBD (>6mm)
-Plain AXR only shows 10% of gallstones
-LFTs, pancreatic enzymes

ASCENDING CHOLANGITIS
-Bloods: FBC, LFT, CRP, Blood cultures
-Contrast CT best for diagnosis
-KUB-XR
-If LFTs are worsening then do ERCP

Question 34

How are different biliary tract diseases managed?

Answer 34

BILIARY COLIC:
-Analgesia (opioid eg morphine (parenterally) and/or diclofenac (suppository) to avoid difficulties in absorption caused by vomiting), rehydration, nil by mouth
-Symptomatic cholelithiasis is usually treated by cholecystectomy (laparoscopy)
-Biliary sphincterotomy and endoscopic stone extraction if the gallbladder has been previously removed, consider biliary stent if stones are irretrievable.

CHOLECYSTITIS:
-Initial treatment includes analgesia (opioid eg morphine (parenterally) and/or diclofenac (suppository) to avoid difficulties in absorption caused by vomiting). IV fluid therapy, nil by mouth and broad spectrum antibiotics eg co-amoxiclav
-Cholecystectomy is the definitive treatment (laparoscopic)
-Open surgery is required if there is gallbladder perforation
-Elderly/ high risk/ unsuitable for surgery, percutaneous cholecystotomy where cholecystectomy can still be done later

ASCENDING CHOLANGITIS:
-Broad spectrum antibiotics (piperacillin/ tazobactam) and decompression of the biliary tree to prevent recurrent infection
-Correction of fluid and electrolyte disturbance, correction of coagulopathy
-Selective antibiotics when cultures have been made
-Endoscopic biliary drainage is ultimately required to treat the obstruction

Silent stones: do elective surgery on those with sickle cell, immunosuppression and diabetes, as well as all calcified/ porcelain gallbladders (pre-cancerous)

Question 35

What are the complications of biliary tract disease?

Answer 35

Gallstone ileus: stone erodes through the gallbladder into the duodenum, it may then obstructs the terminal ileum. AXR shows: air in the common bile duct (pneumobilia), small bowel fluid levels and a stone. Duodenal obstruction is rarer. Treatment is by laparotomy and milking the obstructing stone into the colon or by enterotomy and extraction.
Mucocoele/ empyema: obstructed gallbladder fills with mucus secreted by the gallbladder wall/ pus. Treat with intravenous antibiotics, immediate decompression and removal of the gallbladder.
Mirizzi’s syndrome: a stone in the gallbladder presses on the bile duct causing jaundice
Septic shock in ascending cholangitis

Question 36

What is renal colic and what is the pathophysiology?

Answer 36

Excruciating ‘loin to groin’ pain caused by dilatation, stretching and spasm of the ureter when stones (calculi/crystal aggregates) are present in the kidney, renal pelvis or ureter.

Renal calculi are formed when the urine is supersaturated with salt and minerals such as calcium oxalate, struvite (ammonium magnesium phosphate), uric acid and cystine. 60-80% of stones contain calcium. They vary considerably in size from small ‘gravel-like’ stones to large staghorn calculi. The calculi may stay in the position in which they are formed, or migrate down the urinary tract, producing symptoms along the way.
It is suggested that the initial factor involved in the formation of a stone may be the presence of nanobacteria that form a calcium phosphate shell. The other factor is the formation of Randall’s plaques. Calcium oxalate precipitates form in the basement membrane of the thin loops of Henle; these eventually accumulate in the subepithelial space of the renal papillae, leading to a Randall’s plaque and eventually a calculus.
Bladder stones account for around 5% of urinary tract stones and usually occur because of foreign bodies, obstruction or infection. The most common cause is urinary stasis due to failure of complete emptying

Question 37

What are the presenting features of renal stones?

Answer 37

KEY: Pain which is sudden onset and constant, beginning in the loin/flank and spreading to the groin

SYMPTOMS:
Many stones are asymptomatic and discovered during investigations for other conditions
A stone that is moving is often more painful than a stone that is static
- Rigors
- Fever
- Dysuria
- Haematuria
- Urinary retention
- Nausea/vomiting

SIGNS:
Patient will writhe around and may have tenderness over affected area
Patients are apyrexial in uncomplicated renal colic (pyrexia suggests infection and the body temperature is usually very high with pyelonephritis)
Blood pressure may be low.

Question 38

How are renal stones investigated?

Answer 38

FIRST LINE:
Blood: FBC, U&E, Ca2+, phosphate, glucose, bicarbonate, urate.

Urine: dipstick (usually +ve for blood), MSU (microscopy, culture and sensitivity), pH, 24hr urine for biochemistry to find cause), white cells and nitrates suggest infection.

GOLD STANDARD/ DIAGNOSTIC:
Imaging: non-contrast CT is diagnostic test of choice and helps to rule out other causes of acute abdomen. Use ultrasound for children or pregnant women. Kidney/ureter/bladder (KUB) XR can also be used.

Question 39

How are renal stones managed?

Answer 39

SUPPORTIVE:
- Analgesia (NSAIDs eg diclofenac), IV paracetamol can be used if NSAIDs are contraindicated or not giving sufficient relief, parenteral morphine may be required in severe renal colic pain which works quickly and can provide pain relief in the time taken for an NSAID to work
-Antiemetics if needed
- Rehydration therapy if needed
- Antibiotics if infection
The majority of stones will pass spontaneously but may take 1-3 weeks; patients who have not passed a stone or who have continuing symptoms should have the progress of the stone monitored at weekly intervals.

MEDICAL:
If stones are >5mm or pain is not resolving, commence medical expulsive therapy: alpha blockers (eg tamsulosin) or CCBs (eg nifedipine). A corticosteroid such as prednisolone is occasionally added when an alpha-blocker is used but should not be given as monotherapy.

INTERVENTIONAL:
Approx 1 in 5 stones will not pass spontaneously and will require intervention.
- If medical expulsion therapy is unsuccessful, try extracorporeal shockwave lithotripsy (ESWL) where shockwaves directed over the stone break it apart or basket ureteroscopy. Consider pre-treatment stenting for young people having SWL for renal staghorn stones
-Ureteroscopy can break up the stone with a laser
- Percutaneous or laparoscopic nephrolithotomy can be used as a last resort or for large stones, staghorn calculi and cystine stones.

Question 40

What is acute kidney injury and what is the aetiology?

Answer 40

A syndrome of decreased renal function, measured by serum creatinine and urine output. KDIGO defines it as a rise in creatinine >25micromol/L within 48hrs; rise in creatinine >1.5x baseline within 7 days; urine output <0.5ml/kg/hr for >6 continuous hours. KDIGO defines stage 1,2 and 3 through increasing risks in creatinine levels and drop in urinary output. It is an abrupt loss of kidney function resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes.

Aetiology determined depending on site, either pre-renal (hypoperfusion to kidney - 90%), renal (intrinsic renal disease), post-renal (obstruction to urine).
1. Pre-renal: volume depletion (eg haemorrhage, severe vomiting or diarrhoea, burns, inappropriate diuresis), oedematous states (cardiac failure, cirrhosis, nephrotic syndrome), hypotension (eg cardiogenic shock, sepsis, anaphylaxis), renal hypoperfusion (NSAIDs or COX-2 inhibitors, ACE-i or ARBs, AAA, renal artery stenosis or occlusion, hepatorenal syndrome)
2. Intrinsic renal problem: glomerular disease (glomerulonephritis, thrombosis, haemolytic uraemic syndrome), tubular injury (acute tubular necrosis, nephrotoxins), acute interstitial nephritis due to drugs (NSAIDs), infection or autoimmune disease, vascular disease (vasculitis, cholesterol emboli, renal artery stenosis, renal vein thrombosis, malignant hypertension
3. Postrenal: calculus, blood clot, papillary necrosis, urethral stricture, prostatic hypertrophy or malignancy, bladder tumour, radiation fibrosis, pelvic malignancy, retroperitoneal fibrosis

Question 41

What are the clinical features of acute kidney injury?

Answer 41

KEY: Presentation varies depending on underlying cause and severity of AKI.
Decreased urine volume (oliguria or anuria) and raised in serum creatinine are characteristic of AKI.

SYMPTOMS:
- Oliguria/anuria (abrupt anuria suggests acute obstruction, glomerulonephritis or renal artery occlusion. Polyuria may occur due to either reduced fluid reabsorption by damaged renal tubules, or the osmotic effect of accumulated metabolites)
- Nausea/vomiting
- Dehydration
- Confusion

SIGNS:
- Hypertension
- Large/distended (painless) bladder
- May have either dehydration with postural hypotension and no oedema OR fluid overload with raised JVP and pulmonary and peripheral oedema.
-Pallor, rash, bruising (petechiae, purpura and nosebleeds may suggest inflammatory or vascular disease, emboli or DIC)

Question 42

How is acute kidney injury investigated?

Answer 42

• Detailed history including drugs, occupational, travel, past medical conditions.
• Examination for signs of infection/sepsis, signs of heart failure, fluid status, palpable bladder, underlying systemic disease

DIAGNOSTIC:
- Urine: dipstick for blood, nitrates, leukocytes, glucose and protein. Urine osmolality.
- Blood: FBC, blood film. U&E and creatinine. Coagulation (DIC assoc with sepsis). Creatine kinase (rhabdomyolysis). CRP. Immunology (serum immunoglobulins, ANA, anti-dsDNA, ANCA, anti-GBM). Virology (hep B/C, HIV).
- Imaging: ultrasound (+/- doppler) is imaging modality of choice. CXR, AXR, MR angiography can also be used.

Question 43

How is acute kidney injury managed?

Answer 43

No specific treatment hence management is largely supportive. The cause should be identified and treated where possible.
Patients may require escalation to ITU.

• Fluid and electrolyte balance should be closely monitored and fluid therapy given if appropriate.
• Nephrotoxic drugs should be stopped.
• Monitor creatinine, Na+, K+, Ca2+, phos, gluc.
• Identify & treat infection if present: infection is a significant cause of mortality, strict sepsis control, avoidance of IV lines, bladder catheters and respirators
• Identify & treat complications including hyperkalaemia, acidosis, pulmonary oedema, bleeding.
• Refer to urologist or nephrologist where appropriate for treatment of underlying disease

Renal replacement treatment: if any of the following are not responding to medical treatment: hyperkalaemia, pulmonary oedema, severe metabolic acidaemia, progressive renal failure, uraemic complications, renal transplant, CKD stage 4 or 5. Patients suspected of intrinsic renal disease (vasculitis, primary glomerulonephritis, interstitial nephritis)

Question 44

What are the types of renal cancer?

Answer 44

Renal cell carcinoma (RCC) is the most common tumour of the kidney in adults (80%+). RCC originates from the proximal renal tubular epithelium and can be hereditary or non-hereditary. Other types of renal cancer include transitional cell carcinoma, renal oncocytoma and Wilms’ tumour (commonest in children).

Question 45

What are the clinical features of renal cancer?

Answer 45

50% are found incidentally. 25% have metastases to bone, liver and lung at presentation.
Symptoms and signs: haematuria, loin pain, loin mass. Loss of appetite, malaise, weight loss. Pyrexia of unknown origin is common. Anaemia, polycythaemia and hypercalcaemia may be present.
Rarely, varicocele can occur from the left renal vein compressing the testicular vein.

Question 46

How is renal cancer investigated?

Answer 46

Blood pressure is increased from renin secretion.
Blood: FBC (polycythaemia from EPO), ESR, U&E, ALP.
Urine: RBCs, cytology.
Imaging: ultrasound, CT(diagnostic)/MRI, CXR (to look for metastases, often “cannon ball”).

Question 47

How is renal cancer managed?

Answer 47

Surgery is mainstay of treatment. Radical nephrectomy/nephron-sparing surgery (depending on T-stage on TNM classification).
Cryotherapy and radiofrequency ablation if patient is unsuitable for surgery. RCC is usually radio- & chemo-resistant. For unresectable or metastatic disease: IL2 and T-cell activation therapies, anti-angiogenesis (tyrosine kinase inhibitors) agents eg sunitinib, pazopanib.

Question 48

What are the types of bladder cancer?

Answer 48

Transitional cell carcinoma (TCC) is most common type (90%). Squamous cell carcinomas make up most of the remainder. Bladder cancer is the most common urinary system cancer.
TCC arises from the transitional cells of mucosal urothelium in the bladder.

Question 49

What are the clinical features of bladder cancer?

Answer 49

Symptoms:
- Presenting feature is usually painless haematuria which is gross in 80-90% of patients.
- There may be voiding symptoms and increased feeling of bladder fullness.
Signs:
- Recurrent UTI

Question 50

How is bladder cancer investigated?

Answer 50

• Cystoscopy with biopsy is diagnostic
• CT urogram is also diagnostic and can provide staging
• Urine: microscopy/cytology (cancers may cause sterile pyuria)
• Bimanual examination under anaesthetic may be used to help assess spread
• MRI or lymphangiography can be used to assess nodal involvement in the pelvis

Question 51

How is bladder cancer managed?

Answer 51

Is dependent on the staging.
Tis/Ta/T1: (80% of all patients) diathermy via transurethral cystoscopy/transurethral resection of bladder tumour (TURBT). Consider a regimen of intravesical BCG (stimulates non-specific immune response) for multiple small tumours or high grade tumours. Alternative chemotherapeutic agents include mitomycin, epirubicin and gemcitabine.
T2-3: Radical cystectomy is the gold standard. Radiotherapy gives worse survival rates than surgery but preserves the bladder. Salvage cystectomy can be performed but has worse results than radio/primary surgery. Post-op chemotherapy (eg MVAC - methotrexate, vinblastine, doxorubicin and cisplatin) is toxic but effective. Neoadjuvant therapy (either MVAC or gemcitabine and cisplatin) has improved survival compared with cystectomy or radiotherapy alone.
T4: Usually palliative chemo/radiotherapy. Chronic catheterisation and urinary diversions may help to relieve pain.

Question 52

What are the common prostate cancers and what are the risk factors?

Answer 52

DEFINITION
The most common cancer in men.
Most prostate cancers are adenocarcinomas arising in the peripheral zone of the prostate gland. Most are slow growing (and may only be discovered at autopsy), but some are aggressive. The commonest sites of malignancy are bone and lymph nodes.

AETIOLOGY/RISK FACTORS
- Older age: 80% of men >80yrs have prostate cancer (autopsy studies).
- Family history: if one first degree relative has prostate cancer, the risk is at least doubled.
- Ethnicity: there is higher incidence of and mortality from prostate cancer in men of black African-Caribbean origin compared with white Caucasian men.
- Factors such as food consumption, pattern of sexual behaviour, alcohol consumption, UV light exposure and chronic inflammation may also increase risk.

Question 53

What are the clinical features of prostate cancer?

Answer 53

Usually suspected based on DRE or PSA levels.
Symptoms:
- Local disease: raised PSA on screening, LUTS, UTI.
- Locally invasive disease: haematuria, dysuria, incontinence. Haematospermia. Perineal and suprapubic pain. Obstruction of ureters causing loin pain, anuria, AKI symptoms or CKD. Impotence. Rectal symptoms eg tenesmus.
- Metastatic disease: bone pain/sciatica. Paraplegia secondary to spinal cord compression. Lymph node enlargement. Loin pain/anuria due to ureteric obstruction by lymph nodes. Lethargy (anaemia, uraemia). Weight loss, cachexia.
Signs:
- Advanced disease: general malaise, bone pain, loss of appetite, weight loss, obstructive nephropathy, paralysis due to SCC.
- Abdominal palpation may demonstrate a palpable bladder due to outflow obstruction.
- DRE may reveal a hard, irregular prostate gland. Indications of prostate cancer are asymmetry, nodules, induration, lack of mobility (adhesion to tissue), palpable seminal vesicles.

Question 54

What are the investigations for prostate cancer?

Answer 54

• PSA might be increased, though is normal in 30% of cases of small tumours
• PCA3 urine test is said to be superior to PSA but is expensive so is not used in all cases, usually to decide on repeat biopsy or not.
• DRE
• Transrectal US and biopsy
• Bone scan (metastases)
• CT/MRI

Question 55

How is prostate cancer managed?

Answer 55

MANAGEMENT
Localised or locally advanced:
-Low risk: active surveillance, radical prostatectomy or radical radiotherapy
-High risk: do not offer active surveillance
- If <70yrs, radical prostatectomy has good results
- Radical radiotherapy (with neo/adjuvant hormonal therapy - androgen deprivation therapy) can also be very successful
-Docetaxel chemotherapy: for newly diagnosed non-metastatic high-risk disease
-Do not offer bisphosphonates for the prevention of bone metastases
Metastatic cancer:
-Palliative interventions and coordinated care
-Docetaxel chemotherapy: start within 12 weeks of starting androgen deprivation therapy.
-Bilateral orchidectomy: alternative to continuing LH-releasing hormone agonist therapy

MONITORING AND PROGNOSIS
Adverse effects of radical treatment include sexual dysfunction, urinary incontinence and radiation-induced enteropathy.
Analyse serial PSA levels after radical treatment (6 weeks after treatment then at least every 6 months), if there is biochemical relapse, patents may need radical radiotherapy or hormonal therapy

Question 56

What are the types of testicular cancer?

Answer 56

Testicular lumps are cancer until proved otherwise.
Testicular cancer is the commonest malignancy in males aged 15-44. A contralateral tumour is found in 5% of patients. Most tumours arise from the germ cells.
Types: seminoma (55%, ages 30-65), nonseminomatous germ cell tumour NSGCT (33%, ages 20-30), mixed germ cell tumour (12%), lymphoma.

Question 57

What are the risk factors for testicular cancer?

Answer 57

• Cryptorchidism/testicular maldescent: 10% of all testicular tumours occur in undescended testes, even after orchidopexy.
• Klinefelter’s syndrome (extra X chromosome)
• Family history/genetics (chromosome 12 or TGCT1)
• Male infertility (increases risk by factor of 3)
• Low birth weight, young parent age, multiparity, breech delivery
• Infantile hernia
• Height: taller men are at higher risk of developing germ cell tumours
• Testicular microlithiasis (small intratesticular calcifications seen on ultrasound)

Question 58

What are the features of testicular cancer?

Answer 58

Symptoms:
- Lump in the body of the testis, usually painless (presentation in >95% of patients)
- Testicular pain and/or abdominal pain
- Dragging sensation
- Recent trauma (prompts men to examine testes ergo finding lump, not the cause of cancer)
- Hydrocele
- Gynaecomastia from beta-hCG production
- Metastasis: seminomas metastasis to para-aortic nodes and produce back pain; teratomas undergo blood borne spread to liver, lung, bone and brain

Signs:
- Palpable lump
- Abnormal sensation on examination (not delicate or tender)

Question 59

How is testicular cancer investigated?

Answer 59

Investigations should not delay referral - 2 week referral if malignancy suspected.
- Ultrasound usually confirms diagnosis
- Excision biopsy can help staging via tissue histology
- Thoraco-abdominal CT helps with staging
- Tumour markers are taken preoperatively (as well as US and CXR) including alpha-fetoprotein and beta-hCG. Absence of these does not exclude diagnosis.

Question 60

How is testicular cancer managed?

Answer 60

Surgical:
Radical orchidectomy (inguinal incision, occlude spermatic cord prior to mobilisation to reduce risk of intraoperative spread) - offer prosthesis to all men.

Chemo/Radiotherapy:
- When metastases are present, patients should be referred for immediate chemotherapy
- For most patients, regimen is surgery → radiotherapy → chemotherapy.
- Seminomas are highly radiosensitive; in patients with stage 1 seminomas, orchidectomy and radiotherapy cures 95%.
- NSGCT (even with metastases) is usually cured by 3 cycles of bleomycin + etoposide + cisplatin.

Question 61

What is the pathophysiology of CKD?

Answer 61

The definition of CKD is based on the presence of kidney damage (i.e albuminuria) or decreased kidney function (ie low GFR) for 3 months or more, irrespective of clinical diagnosis.

CKD is initially renal insufficiency which may progress to renal failure (end-stage renal disease). Initially as renal tissue loses function, there are few noticeable abnormalities because the remaining tissue increases its performance (renal adaptation). Decreased renal function interferes with the kidneys’ ability to maintain fluid and electrolyte homeostasis. The ability to concentrate urine declines and is followed by decreasing ability to excrete excess phosphate, acid and potassium.
Creatinine and urea: plasma concentrations which are highly dependent on glomerular filtration begin a hyperbolic rise as GFR diminishes. Levels are high and usually associated with systemic manifestations (uraemia).
Sodium and water: balance is maintained by increased fractional excretion of sodium in urine and a normal response to thirst. Plasma concentration of sodium is typically normal and hypervolaemia is infrequent. Heart failure can occur due to sodium and water overload.
Potassium: for substances whose secretion is controlled mainly through distal nephron secretion, renal adaptation usually maintains plasma levels at normal.
Calcium and phosphate: abnormalities of calcium, phosphate, PTH and Vitamin D metabolism can occur, as can renal osteodystrophy. Decreased renal production of activated Vitamin D contributes to hypoglycaemia. Decreased renal excretion of phosphate results in hyperphosphataemia. Secondary hyperparathyroidism is common and can develop in renal failure before abnormalities of calcium or phosphate concentrations occur.
Renal osteodystrophy: abnormal bone mineralisation resulting from hyperparathyroidism, calcitriol deficiency, elevated phos or low serum calcium. Usually takes the form of increased bone turnover due to hyperparathyroid bone disease (osteitis fibrosa). Calcitriol deficiency may cause osteopenia or osteomalacia.
pH and bicarbonate: moderate metabolic acidosis is characteristic. Acidosis causes muscle wasting due to protein catabolism, bone loss due to bone buffering of acid, and accelerated progression of kidney disease
Anaemia: characteristic. It is normochromic-normocytic. It is usually caused by a deficient EPO production due to a reduction of functional renal mass. Other causes include deficiencies of iron, folate and vitamin B12

Question 62

What are the clinical features of CKD?

Answer 62

SYMPTOMS:
CKD is usually asymptomatic and often unrecognised because there are no specific symptoms
-May be discovered by chance following a routine blood or urine test
-Specific symptoms usually develop in severe CKD: anorexia, nausea, vomiting, fatigue, weakness, pruritus, lethargy, peripheral oedema, dyspnoea, insomnia, muscle cramps. Pulmonary oedema, nocturia, polyuria and headache
-Sexual dysfunction is common
-Hiccups, pericarditis, coma and seizures are only seen in very severe CKD

SIGNS:
-Characteristics of underlying cause (eg SLE, severe arteriosclerosis, hypertension) or complications of CKD (eg anaemia, bleeding diathesis, pericarditis)
-Increased skin pigmentation or excoriation, pallor, hypertension, postural hypotension, peripheral oedema, LVH, PVD, pleural effusions, peripheral neuropathy and restless legs syndrome

Question 63

How is CKD classified?

Answer 63

Kidney function is assessed using GFR and Albumin: creatinine ratio (ACR) categories. Increased ACR and decreased GFR are associated with increased risk of adverse outcomes.
Stage 1: normal - eGFR >90 with other evidence of chronic kidney damage
Stage 2: mild impairment - eGFR 60-89 with other evidence of chronic kidney damage
Stage 3a: moderate impairment - eGFR 45-59
Stage 3b: moderate impairment - eGFR 30-44
Stage 4: severe impairment - eGFR 15-29
Stage 5 established renal failure (ERF) - eGFR less than 15 or on dialysis

Other evidence of chronic kidney damage:
-Persistent microalbuminuria
-Persistent proteinuria
-Persistent haematuria
-Structural abnormalities of the kidneys
-Biopsy-proven chronic glomerulonephritis

Question 64

How is CKD investigated?

Answer 64

eGFR should be monitored regularly. Proteinuria should be assessed at least annually. Annual formal assessment of cardiovascular risk factors

Haematology:
-Normochromic, normocytic anaemia (Hb falls with progressive CKD), WCC and platelets usually normal

Biochemistry:
-Plasma glucose: to detect undiagnosed diabetes or assess control of diabetes
-Normal/ low sodium, raised potassium, low bicarbonate, high phosphate, any level of serum calcium
-Serum albumin: hypoalbuminaemia in patients who are nephrotic and/or malnourished
-Serum alk Phos: raised when bone disease develops, Serum PTH: rises progressively with declining renal function
-Dysplipidaemia is common

Assessment of renal function:
-eGFR
-Serum urea varies significantly and serum creatinine level can remain in the normal range despite loss of kidney function so these are poor markers
-Gold standard is an isotopic GFR, but it is expensive and not widely available

Serology:
-Autoantibodies: ANA, c-ANCA, p-ANCA, anti-GBM (very suggestive of goodpasture’s), serum complement
-Hepatitis and HIV serology
Other:
-ECG and echo: asses LVH and ischaemia, assess cardiac function

Urine:
-Urinalysis: dipstick proteinuria may suggest glomerular or tubulointerstitial disease. Urine sediment with RBCs and red blood cell casts suggests proliferative glomerulonephritis
-Pyuria and/or white cell casts suggest interstitial nephritis or UTI
-Measure proteinuria, ACR

Imaging:
-Plain abdominal X Ray: may show radio-opaque stones or nephrocalcinosis
-Renal US: small echogenic kidneys in advanced CKD, normally initially large and then become normal in size in diabetic nephropathy, structural abnormalities eg polycystic kidneys,
-CT: define renal masses and cysts
-MRI: renal vein thrombosis
Renal biopsy

Question 65

How is CKD managed?

Answer 65

General:
-Encourage exercise, achieving a healthy weight, smoking cessation, low salt diet
-Patients with diabetes and CKD should achieve good glycaemic control (aim HbA1c<53)
-Avoidance of nephrotoxins eg IV radiocontrast agents, NSAIDs, aminoglycosides
-Immunise against influenza and pneumococcus
-Review all medication
-Treat any complications eg anaemia, acidosis, oedema.

CVD prevention:
-Statins: atorvastatin for primary or secondary prevention in those with CKD
-Folic acid and B vitamin supplements: for patients considered nutritionally at risk from deficiency
-Oral antiplatelets and anticoagulants

BP control:
-ACE-i or ARBs for people with CKD and diabetes, hypertension, high ACR. Stop if serum potassium increases too high

Mineral and bone disorders:
-Offer bisphosphonates if indicated for the prevention and treatment of osteoporosis in people stage 3b or above
-Offer cholecalciferol to treat vitamin D deficiency
-Offer phosphate binders (calcium acetate) in patients with hyperphosphataemia as this can lead to the development of secondary hyperparathyroidism

RENAL REPLACEMENT THERAPY
Haemodialysis, peritoneal dialysis, chronic ambulatory peritoneal dialysis and renal transplantation

Question 66

What is the aetiology and pathophysiology of UTI?

Answer 66

In normal genitourinary tracts, strains of E.coli with specific attachment factors for transitional epithelium of the bladder and ureters account for 75-95% of cases. The remaining gram-negative urinary pathogens are usually other enterobacteria, typically Klebsiella or Proteus mirabilis, and occasionally Pseudomonas aeruginosa. Amongst gram-positive bacteria, Staphylococcus saprophyticus is isolated in 5-10% of bacterial UTIs.
(Urethritis is usually caused by sexually transmitted organisms including Chlamydia trachomatis, Neisseria gonorrhoeae or non-gonococcal urethritis.)

PATHOPHYSIOLOGY
The urinary tract, from the kidneys to the urethral meatus, is normally sterile and resistant to bacterial colonisation despite frequent contamination of the distal urethra with bacteria from the colon. The major defense against UTI is complete emptying of the bladder during urination. Other mechanisms that maintain the sterility include urine acidity, the vesicoureteral valve, and various immunological and mucosal barriers.

About 95% of UTIs occur when bacteria ascend the urethra to the bladder and, in the case of pyelonephritis, ascend the ureter to the kidney. The remainder of UTIs are haematogenous. Systemic infection can result from UTI, particularly in older patients. About 6.5% of cases of hospital-acquired bacteremia are attributable to UTI.

Question 67

What are the clinical manifestations of UTI based on location?

Answer 67

CYSTITIS:
Symptoms: increased frequency, dysuria, urgency, suprapubic pain, polyuria, haematuria.
Signs: suprapubic tenderness.
PYELONEPHRITIS:
Symptoms: fever, rigor, vomiting, loin pain/tenderness, costovertebral pain, cystitis symptoms (increased frequency, urgency), septic shock.
Signs: fever, abdominal/loin tenderness.
PROSTATITIS:
Symptoms: pain in the perineum, rectum, scrotum, penis, bladder and lower back. Malaise, nausea, urinary symptoms.
Signs: fever. Swollen/tender prostate on PR.
URETHRITIS:
Symptoms: dyspareunia (pain on sexual intercourse), dysuria, increased frequency/urgency, vaginal/urethral discharge, itch.
Signs: abnormal discharge, redness around urethra.

Question 68

How are UTIs investigated?

Answer 68

In non pregnant women with >3 symptoms of cystitis and no abnormal vaginal discharge, treat empirically without further tests.
Dipstick: use in non-pregnant women <65yrs with less than 3 symptoms. A negative dipstick reduces probability of UTI to <20%. Do not use in pregnant women.

MSU culture: use in pregnant women, men and children, and people who fail to respond to empirical antibiotics.

Bloods: use if systemically unwell. FBC, U&E, CRP, blood culture (positive in only 10-25% of pyelonephritis). Consider a fasting glucose.

Imaging: consider USS and urology referral for assessment (cystoscopy, urodynamics, CT) in men with upper UTI; patients who fail to respond to treatment; recurrent UTI; pyelonephritis; unusual organism; persistent haematuria.

Question 69

How are UTIs managed?

Answer 69

NON-PREGNANT WOMEN:
Cystitis:
1. If 3+ symptoms of cystitis and no abnormal vaginal discharge, treat empirically with 3 day course of nitrofurantoin or trimethoprim.
2. If first line empirical treatment fails, culture urine and treat according to antibiotic sensitivity.

Upper UTI:
1. Take urine culture and treat initially with broad spectrum antibiotics (eg co-amoxiclav) according to local guidelines/sensitivities
2. Hospitalisation should be considered due to risk of antibiotic resistance. Avoid nitrofurantoin as it does not achieve effective concentrations in the blood.

PREGNANT WOMEN:
Get expert help - UTI in pregnancy is associated with preterm delivery and intrauterine growth growth restriction.
1. Treat with an antibiotic and refer to local guidelines (avoid ciprofloxacin and trimethoprim in first trimester, avoid nitrofurantoin in third trimester).
2. Confirm eradication of bacteriuria.

MEN:
1. Treat lower UTI with a 7 day course of trimethoprim or nitrofurantoin
2. If symptoms suggest prostatitis, consider a longer (4 week) course of a fluoroquinolone (eg ciprofloxacin) due to ability to penetrate prostatic fluid.
3. If upper or recurrent UTI, refer to urology.

Question 70

What is the pathogenesis of type 2 diabetes?

Answer 70

Insulin secretion is inadequate because patients have developed resistance to insulin. Hepatic insulin resistance leads to an inability to suppress hepatic glucose production and peripheral insulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and post-prandial hyperglycaemia. Often, insulin levels are very high, especially in early disease, later in the course of the disease, insulin levels may fall, further exacerbating the hyperglycaemia.

Question 71

What are the clinical manifestations of type 2 diabetes?

Answer 71

KEY: Polydipsia and polyuria
SYMPTOMS:
Patients are often asymptomatic so that their condition is only diagnosed during routine testing.
Some patients’ presenting symptoms can be those of diabetic complications
-Polyuria: the result of an osmotic diuresis that results when blood glucose levels exceed the renal tubular reabsorptive capacity.
-Weakness, fatigue and altered consciousness, coma
-Nausea, vomiting and blurred vision
SIGNS:
-Glycosuria
-Recurrent infections

Question 72

How is T2DM investigated?

Answer 72

GOLD STANDARD/ DIAGNOSTIC:
-HBA1c: >48mmol/mol. A value less than 48 does not exclude diabetes, but it would then be diagnosed using glucose tests instead. Diagnosis should never be based on a solitary abnormal HBA1c or glucose test, and at least one other additional abnormal test is essential.
-Fasting glucose level: >7mmol/L for patients for whom HBA1c is contraindicated eg end stage chronic kidney disease
-Random Plasma glucose: >11mmol/L

Question 73

How is T2DM managed?

Answer 73

1st LINE:
-Lifestyle modification: Healthy diet, regular physical activity, weight control, avoidance of tobacco
-Metformin: standard release

2nd LINE:
If HbA1c rises to above 58mmol/mol, consider dual therapy with either:
1. Metformin + DPP4 inhibitor (sitagliptin)
2. Metformin + Pioglitazone (thiozoladindione)
3. Metformin + sulphonylurea (increase insulin secretion)
4. Metformin + SGLT2 inhibitors (glifazon)

3rd LINE;
Consider triple therapy with:
1. Metformin + DPP4 inhibtor + sulphonylurea
2. Metformin + Pioglitazone + sulphonylurea
3. Metformin + either sulphonylurea/pioglitazone + SGLT2 inhibitor
4. Insulin therapy: often required after 5-10 years from diagnosis although it is less likely in people who have followed the lifestyle modifications successfully

Question 74

What are the main complications of diabetes?

Answer 74

CARDIOVASCULAR DISEASE
CCS/ACS, Cerebrovascular events, Peripheral arterial disease
Asses vascular risk, blood pressure control and smoking cessation. Check plasma lipids. Vascular disease is the chief cause of death. MI in 4 fold commoner in diabetes and is more likely to be silent. Stroke is twice as common. Women are at high risk, diabetes removes vascular advantage of female sex. Address other risk factors: diet, smoking, hypertension. Suggest a statin for all, even if no overt IHD, vascular disease or microalbuminuria. Aspirin reduces vascular events in the context of secondary prevention.

DIABETIC NEPHROPATHY
Microalbuminuria is when urine dipstick is negative for protein, but the urine albumin to creatinine ratio is greater than/ equal to 3mg/mmol, reflecting early renal disease and increased vascular risk. Inhibiting RAAS with ACEI or ARBs, even if BP is normal, protects the kidney. Spironolactone may also help.

DIABETIC RETINOPATHY
Blindness is preventable. Annual retinal screening is mandatory for all patients. Refer to an ophthalmologist if pre-proliferative changes or if there is any uncertainty at or near the mecula

DIABETIC NEUROPATHY / DIABETIC FOOT
Decreased sensation in the stocking distribution. Sensory loss is patchy so examine all areas, absent ankle jerks, neuropathic deformity eg charcot joint, claw toes, loss of transverse arch caused by loss of pain sensation leading to increased mechanical stress and repeated injury. Swelling, instability and deformity. If the foot pulses cannot be felt, do doppler pressure measurements, any evidence of neuropathy or vascular disease increases the risk of foot ulceration. If infected, treat infection, surgery for abscess, deep infection or gangrene.
Autonomic neuropathy: arrhythmias, decreased cerebrovascular autoregulation, gastroparesis, urine retention, erectile dysfunction, postural hypotension

RECURRENT INFECTIONS / SKIN
Particularly urinary tract and skin eg cellulitis, boils and abscesses, TB and mucocutaneous candidiasis.

Question 75

What is hyperosmolar hyperglycaemic state?

Answer 75

A state of extreme hyperglycaemia seen in type 2 diabetes, accompanied by dehydration that can be severe. Typically triggered by illness in a patient with type 2 diabetes, or a patient with previously unknown type 2 diabetes. Emergency hospital treatment is required to control blood glucose levels and to treat the dehydration, and the underlying precipitating cause. There is a significant mortality, especially in the elderly and patients with other disorders eg vascular disease. While insulin is required as part of the initial emergency treatment, it is not often required as long-term treatment.

Endogenous insulin levels are reduced but are still sufficient to inhibit hepatic ketogenesis, whereas glucose production is unrestrained. Patients present with profound dehydration secondary to an osmotic diuresis, and a decreased level of consciousness which is directly related to the elevation of plasma osmolality.