All Questions Flashcards
The main risk factor for the development of late-onset dementia in people over the age of 75 years is:
A. homozygosity for apolipoprotein E4 (APOE4).
B. mild cognitive impairment.
C. advanced age.
D. hypertension.
E. cerebral atrophy on computed tomography (CT) scan.
Answer C
Only two big risk factors to worry about for Alzheimer’s – age, and genetics. APOE4 is the biggest genetic risk factor for AD, with 10-30 times increased risk. APOE4 helps get amyloid precursor protein inside the cells, which are chopped up by proteases and then these bits hang around, causing general dysfunction. It’s also thought that APOE4 limits clearance of amyloid. Not everyone with AD has APOE4 and vice versa, so it’s not the answer altogether.
There are a few different genetics to be concerned with:
• APP gene on chromosome 21
o Alzheimer’s associated with Down’s syndrome
o APP = amyloid precursor protein
o Broken down into small bits, including A-beta amyloid that gets deposited in plaques
• Presenilins
o PS-1 and PS-2
o Result in early onset AD
o Elevated plasma levels of A-beta 42 (which is the pathogenic one)
• APOE4
o Strong association with AD in general population
o Single most important biological marker associated with risk for AD
Single strongest risk factor for dementia is increasing age.
10% of those over 70 have significant memory loss – in more than half, the cause is AD.
In those over 60, think of AD, then vascular dementia, then dementia assoc. with Parkinson’s. In those under 60, FTD is pretty close to AD in terms of the most common cause. Chronic intoxication is another one to keep in mind.
Mild cognitive impairment is officially defined as a cognitive problem that has begun to subtly interfere with the activities of daily living. Conversion rate from MCI to AD is about 12 percent per year. There are a couple of factors that determine the MCI to AD conversion:
• memory deficit > 1.5 std devs from the norm
• family history of dementia
• presence of APOe4
• small hippocampal volumes
QUIZ
Dementia, peripheral neuropathy, and white lines on the nails?
What caused the dialysis dementia syndrome?
What is dementia pugilistica?
Always look for the reversible cause – about 1 in 5 cases of ‘dementia’ can be reversed.
A 60yr old male presents with worsening dysphagia for solid and liquid food. Manometry is shown above (reference normal on left, patient tracing on right). The most likely diagnosis is:
A. Hiatus Hernia
B. GORD
C. Achalasia
D. Distal oesophageal malignancy
E. Presbyoesophagus
Answer C- Achalasia
From the diagram:
- Impaired relaxation of LES
- ?lack of peristalsis (v. low amplitude waves in esophagus; ?
Esophageal manometry study (EMS): General concepts
Definition:
- Gold standard assessment of esophageal motor function via measurement of esophageal pressure
- It best measures:
o Integrity of peristalsis
o UES and LES relaxation
- Never a 1ry investigation
Indications:
- To evaluate suspected disorders of a) motility or b) peristalsis of the esophagus:
o Achalasia, diffuse esophageal spasm, nutcracker esophagus, hypertensive lower esophageal sphincter
- Px typically present with dysphagia (both solids and liquids)
Procedure:
- A nasopharyngeal pressure-detecting recording catheter is inserted past the lower esophageal sphincter. The catheter is then slowly withdrawn, whilst the px does certain maneuvers:
o Deep breathing; swallowing (water)
- Takes ~45min
High resolution manometry (HRM):
- Significantly reduces procedure time (~10min) and enhanced patient comfort
Distinct manometric features found in:
- 1. Achalasia
- 2. Diffuse esophageal spasm
Manometric analysis
Pharynx and UES assessment:
- Mainly: UEC relaxation; integrity of pharyngeal persitalsis, intrabolus pressure (IBP)
o IBP: increased by impairment of opening- eg crcipharyngeal bars, zenker’s diverticulum; or relaxation- cricopharyngeal acalasia
- UEC relaxation (most critical element of assessment):
o and its timing in relation to pharyngeal peristalsis (relaxation starts as pharyngeal peristaltic wave sweeps through hypopharynx)
Nadir pressures 1-2mmHg above hypopharyngeal pressure; duration 0.4-0.5s
Esophageal peristalsis:
- Mainly: 1) amplitude and 2) propagation of pressure waves
o Amplitude: from end-expiratory pressure to peak of pressure wave; major determinant of esophageal clearance
Measurements:
• Min 30mmHg (distal); 12mmHg (prox)
•
• >180mmgh hypertensive (significance unclear)
Wave:
• Typically single-peaked (double peaked not uncommon, >3 rare and abnormal- happens in chest pain)
• Duration
o Propagation: timing of major upstroke of the pressure wave (correlates with lumen occlusion)
Normal: 2-4cm.s-1
>6cm.s-1 poor esophageal clearance
‘Simultaneous’: isobaric vs nonisobaric:
• Isobaric: low amplitude, similar amplitudes in adjacent sites
o nonlumen occluding contractions
• Nonisobaric: varying amplitudes and configuration
o lumen-occluding contractions
LES function:
- Mainly: axial location, basal pressure (relative to gastric pressure), degree of relaxation
o Basal pressure:
N.B: Basal pressure can vary widely within individuals and according to method ( normal vales vary).
o LES relaxation: Most important aspect of LES function
Measured as nadir pressure (should be ‘complete’ i.e 0mmHg, but up to 7mmHg has been recorded at max relaxation);
Manometric features of common disorders:
Pharyngeal motor disorders: Pharnyx or UES
1. Cricopharyngeal Bar:
- radiological characterisation of prominent indentation on lateral views of pharynx, due to fibrosis of the cricopharyngeal muscle and failed opening and thus prominence of this muscle
- Clinically asymptomatic
- Manometry: ↑IBP
2. Cricopharyngeal achalasia:
- Manometry: Impaired UES relaxation (uncommon) lesions affecting medullary swallowing center
3. Zenker’s Diverticulum (pharyngoesophageal diverticulum/pharyngeal pouch)
- A false diverticulum (i.e doesn’t involve all layers of esophagus)
- A radiological diagnosis (manometry is diagnostically non-contributory)
- Manometry: Imapired UEC opening (‘pulsion diverticulum’); normal relaxation or UES
Esophageal motor disorders:
1. Achalasia: [Figure 10]
- Manometrical features (2):
o 1. Incomplete LES relaxation [the main abnormality];
typically partial relaxation present
o 2. Absent peristalsis
only low-amplitude simultaneous isobaric pressure waves
N.B aperistalsis alone can be due to: scleroderma, amyloidosis, DM, reflux etc
o + 3. basal intraesophageal pressure> higher than intragastric pressure
usually 20 to esophageal retention: will disappear if px regurgitates retained contents
o + 4. ↑ basal LES pressure
- Incomplete LES relaxation (with swallowing)
- Absent peristalsis
- Intraesophageal pressure>intragastric
pressure - Diffuse Esophageal spasm
- manometric criteria not well defined
- Essential feature: excessive proportion of simultaneous pressure waves in presence of persitalsis
Comments on answers:
A. Hiatus Hernia:
- Manometry: double high pressure zone “double hump”
B. GORD:
- Manometry not recommended in routine diagnosis of GORD
- Wide variety of abnormalities described:
o Dysfunction of LES (eg hypotension, ↑transient relaxation; shorter length)
o Defective peristalsis
D. Distal oesophageal malignancy:
- Manometry obviously not recommended as routine diagnosis
- Can present like achalasia (non relaxation of LES etc)
E. Presbyoesophagus:
- Failure of peristalsis in an ‘old’ oesophagus (age-related changes)
- Manometry: mainly mild decrease in amplitude (
In the general community, which of the following is the major pathogenic factor for reflux oesophagitis?
A. Excessive acid secretion
B. Excessive transient lower oesophageal sphincter relaxations
C. Presence of a hiatus hernia
D. Impaired oesophageal motility
E. Impaired gastric emptying
Answer B – Excessive transient lower oesophageal sphincter relaxations
Discussion
Pathogenesis of Reflux Oesophagitis:
Primary event = exposure of oesphageal mucosa to acid / pepsin from the stomach
Three dominant mechanisms are:
- Transient lower oesophageal sphincter relaxations (tLESRs)
- physiological mechanism of belching
- accompanied by crural diaphragmatic inhibition, oesophageal shortening and contraction of costal diaphragm
- vagally-mediated reflex
- unclear why some individuals have increased number of tLESRs
- hypothesised increased number may not be as important as frequency of acid reflux with tLESR
- potential treatment with GABA type B agonists eg. baclofen - Reduced Lower Oesphageal Sphincter Mechanism
-hypotension lower oesophageal sphincter (primary or secondary impairment)
-crural diaphgram weakness (less common)
*normal resting tone of the LOS 10-30mmHg
-only a minority of GORD patients have a grossly hypotensive LOS
-gastric distension, foods such as fat / chocolate / caffeine / ETOH, smoking, drugs can lower LOS pressure - Anatomical disruption of gastrooesphageal junction, often associated with hiatus hernia
- patient’s lose diaphragmatic crura contraction which contributes to oesophogastric junction pressure in addition to LOS pressure
- thought that HH unlikely to result in severe incompetence unless combined with reduced LOS
Other: obesity, pregnancy (note link between GORD and H.pylori remains incompletely defined)
Which of the following is most likely to cause predominantly zone 1 (periportal) rather than zone 3 (centrilobular) liver pathology?
A. Alcohol
B. Paracetamol
C. Morbid obesity
D.Budd-Chiari syndrome
E. Primary biliary cirrhosis
Answer E- Primary biliary cirrhosis
The liver
Anatomical unit: Hepatic lobule
A hepatic lobule (hexagonal) is defined as having a central vein at its centre and portal triads at the corners.
- Hepatocytes are arranged in irregular, branching,
interconnected plates around a central vein.
- The portal triads (branch of hepatic artery, portal vein, bile
duct) lie at the corners of these lobules
- Blood from the portal triad drains into sinusoids (which is
endothelium lined, with occasional Kupffer cells) towards the
central vein in the middle of each lobule
- Bile is secreted by hepatocytes , enters bile canaliculi bile
ductules which pass to the periphery and drain into the bile
duct at the portal triad R and L hepatic ducts common
hepatic duct
N.B Bile flows in the opposite direction to blood flow
Functional unit: Hepatic Acinus
The hepatic acinus is the functional unit of the liver and is differentiated into 3 distinct zones centred around the main branches of the portal triad.
Blood flows from the portal triad to:
- Zone 1 (periportal) hepatocytes around the portal
vein Zone 2 heptocytes through sinusoids then
- Zone 3 hepatocytes (centrilobular) near/around the
central vein
Functionally this means:
- Zone 1: well oxygenated, first contact with toxins or
bile blockage etc
- Zone 3: least oxygenated, susceptible to ischaemia
Cause Region of change (predominant) Histology
Alcohol Zone 3 (centrilobular) Hallmark of all stages is predominant zone 3 changes (regardless of type eg alcoholic hepatitis/cirrhosis/fatty liver)
Fatty liver: accumulation of fat within perivenular hepatocytes fat in entire hepatic lobule. Progressive injury= giant mitochronida, fibrosis, macrovesicular fat
Alcoholic hepatitis: hepatocyte injury characterised by
- ballooning degeneration; spotty necrosis; PMN infiltrate, fibrosis (perivenular, perisinusoidal space of Disse); + Mallory bodies
Paracetamol Zone 3 Area of greatest concentration of CYP2E1in zone 3 site of maximal production of NAPQI (N-acetly p-buzoquincaine) significant for o/d
Paracetamol converted to notoxic metabolites in liver+ (small portion)
oxidized by CYP450
CYP2E1 (and 3A4) convert ~5% to NAPQI [normally
detoxified by conjugation with glutathione= cysteine and
mercapturic acid conjugates]
Overdose sulphate and glucuronide pathways saturated more
paracetamol shunted to produce NAPQI]
Morbid obesity Zone 3 Indistinguishable from alcoholic-liver disease (i.e not hep or cirrhosis)
Budd-Chiari syndrome Zone 3 Clinical pic caused by occlusion of hepatic veins [abdo pain, ascites, hepatomegaly] thrombosis (1ry), compression etc (i.e ischaemic injury).
Histo: centrizonal congestion, necrosis, haemorrhage.
Primary Biliary cirrhosis Zone 1 Autoimmune destruction of the bile ducts with inflammation characterised by:
- intraepithelial lymphocytes
- Periductal epithelioid graumulomata
Stages (4):
- Stage 1 (Portal stage): normal size triads, portal inflam, bile duct
damage (subtle)
- Stage 2 (Periportal stage): enlarged triads; periportal fibrosis/inflame +
proliferation of small bile ducts
- Stage 3 (Septal stage): Active and/or passive fibrous septa
- Stage 4 (biliary cirrhosis): nodules, garland pattern
Which of the following agents is most likely to induce weight loss when used to treat T2DM?
A. Acarbose
B. Glargine insulin
C. Glimepiride
D. Metformin
E. Pioglitazone
Answer D- Metformin
Oral hypoglycaemics:
Agent 1ry mechanism Features of drug Risk of hypo Risk with renal f
Biguanides
Metformin ↓ hepatic glu production Weight neutral, but favours loss. CV benefit in obese
Lactic acidosis,GI:diarrhoea,
Contraindicated eGFR
Sulphonylureas
Glimepiride Stimulate insulin secretion Weight gain
Accelerated beta cell loss Mod-high
Glimep, Gliben
Mod: gliclazide
Low: glipizide
↑ risk hypo:
Gliclazide; Gliben
Minimal risk:
Glipizide, Glimep
a-glucosidase inhibitor
Acarbose Decreases glu absorption Weight neutral
GI intolerance (mainly flatulence) Mod if used with sulphonylureas Contraindicated eGFR
Glitazones
Pioglitazone
Rosiglitazone ↓ insulin resistance; improves B cell function Weight gain
Exacerbates CCF, Rare LFT abnormalities, anaemia
? ↑ AMI with Rosi Low No accumulation
Glitinides
Repaglinide Mod No accumulation
DPP-4 inhibitor
Sitagliptin Inhibits breakdown of GLP1 Weight neutral
“Weakly effective” Low Dose reduction if severe
GLP1 analogue
Exanatide/Byetta Stimulates insulin secretion and B cell mass+ function;
↓glucagon; ↑satiety Weight loss
Delayed gastric emptying, nausea
?CV benefit (trials ongoing)
?Preservation of beta cell function Mod Contraindicated eGFR
Insulin:
- One trial of comparison Levemir vs Glargine:
o Px on glargine gained more weight on average than Levemir treated px (?non significant)
- Retrospective cohort study:
o Weight on insulin highly correlated with max weight before diabetes
Which one of the following is the predominant stimulus to gastric acid secretion in a healthy individual?
A. Acetylcholine
B. Gastrin
C. Histamine
D. Calcium
E. Somatostatin
Answer B- Gastrin
Histology of stomach
General:
- The surface of the mucosa is a layer of epithelial cells, which extend down into the lamina propria where they form columns of secretory cells (gastric glands) that line many narrow channels called gastric pits.
Exocrine gland cells (3 types): gastric juice
- Surface mucous cells: simple columnar epithelial cells
o Secrete mucus
- Parietal cells:
o Produce intrinsic factor, and hydrochloric acid
- Peptic cells/chief cells:
o Secretes pepsinogen and gastric lipase
- [G cells]: enteroendocrine cell
o Mainly in pyloric antrum; secretes gastrin
- [Enterochromaffin-like cells: ECF]:
o Lies in deep recesses of parietal glands, secretes histamine
Gastric acid secretion
Gastric acid:
- Composed of HCL, KCL, NaCL; produced by the parietal cells
3 phases:
- 1. Cephalic phase: Parasympathetic stimulation (30% of gastric secretion)
o Reflexes stimulated by sight, smell, taste or thought of food
o Cerebral cortex and feeding centre in hypothalamus: sends nerve impulses to the medulla oblongata
o transmits impulses to parasympathetic preganglionic neurons in the vagus nerve
o stimulates parasympathetic postganglionic neurons in submucosal plexus
o stimulates gastric glands to secrete pepsinogen, hydrochloric acid, mucus into stomach chime; gastrin into the blood
- 2. Gastric phase: Food reaches the stomach (60% of gastric secretion)
o Stretch receptors detect distension of stomach and chemoreceptors monitor pH of chime (↑pH)
o activates parasympathetic and enteric neurons in submucosal plexus ACH
causes continuation of gastric juice stimulation (from parietal, chief, mucous cells)
stimulates gastrin release by G cells (also stimulated by chemicals in food eg caffeine) stimulates growth of gastric glands and secretion of large amounts of gastric juice
o ACH and gastrin (G cells):
stimulate parietal cells to secrete more HCl (in the presence of histamine)
o Histamine (paracrine substance released by mast cells in lamina propria)
acts on nearby parietal cells (H2 receptor) acts synergistically with ACh and gastrin to enhance their effects.
- 3. Intestinal phase: 10% of gastric secretion
o Stretch receptors detect distension of duodenum; chemoreceptors detect fatty acids/glucose:
triggers enteroendocrine cells in SI to release secretin and cholecystokinin (CCK)
Secretin: decreases gastric secretion, stimulates secretion of sodium bicarb from pancreas
CCK: inhibits stomach emptying
Stimulation of gastric secretion
Parietal cells have receptors for 3 stimulators of acid secretion:
- ACH: The major neural stimulator
o released by parasympathetic NS via vagus nerve; acts on muscarinic type receptor)
- Gastrin: the major endocrine stimulator
o Large polypeptide from gastrin (G) cells in pyloric glands.
o Gastrin is transported to the enterochromaffin-like cells (ECL) of the stomach release of histamine stimulates more gastric HCl secretion
- Histamine: (H2 receptor): The major paracrine stimulator
o “most important positive regulation mechanism of the secretion of gastric acid in the stomach”
o Stimulated by gastrin and ACH release; inhibited by somatostatin
o Directly regulates the rate of formation and secretion of HCl by the parietal cell
Mechanism: activates adenylate cyclase ↑cAMP and activation of protein kinase A (PKA)
- Other: unclear physiological role
o Calcium, Bombesin: stimulate gastrin secretion
o Enkephalin
Inhibition of secretion:
- Somatostatin: The main inhibitor of acid secretion
o Released from D cells
o inhibits secretion of both gastrin and histamine; has a direct inhibitory effect on parietal cells
- Vasoactive intestinal peptide (VIP);
- Gastric inhibitory peptide (glucose-dependent insulinotropic peptide)
- Secretin
Comments on answers
A. ACH: dose stimulate gastric acid production, not as much as others
C. Histamine: regulatory mechanism for the amount of gastric acid secretion there will be
D. Calcium: stimulates gastric secretion, but unclear physiological role
E. Somatostatin: inhibits gastric acid secretion directly from parietal cells
Which of the following secondary causes of hyperlipidaemia is most likely to cause a predominant increase in LDL-cholesterol?
A. Protease inhibitor therapy
B. T2DM
C. Obesity
D. Alcohol excess
E. Hypothyroidism
Answer E- Hypothyroidism
Secondary causes of hyperlipidaemia
- Cholesterol:
- Hypothyroidism
- Nephrotic syndrome
- Cholestatic Liver Disease
- Cyclosporin - Triglyceride:
- Alcohol
- Oral estrogen, tamoxifen, aromatase inhibitors
- Diabetes
- Drugs: BB, steroids, olanzapine, protease inhibitors, clozapine, interferons, sirolimus - HDL lowering:
- Anabolic steroids
- Smoking
Review of specifics
Mainly hypercholesterolaemia
1. Hypothyroidism:
- Common cause of hyperlipidaemia, frequently associated
- Causes: ↑cholesterol (+↑ TG)
- Features:
o Severity increases with the severity of the hypothyroidism
o One study (268 px) with 1ry hypothyroidism:
- ↑cholesterol in 56%; ↑chol +TG in 34%, ↑TG in 1.5%
- Only 8.5% had a normal lipid profile
o Reversal of hypothyroidism with thyroid hormone replacement leads to correction of hyperlipidaemia
- Serum TSH should be measured in all px with dyslipidemia
2. Nephrotic syndrome:
- Causes: ↑cholesterol
- Features:
o Major abnormality is ↑ hepatic production of lipoproteins (induced by part by the fall in plasma oncotic pressure):
- Endogenous pathway: VDLD IDL LDL via lipoprotein
o Diminished lipid catabolism may play a contributory role
3. Cholestastic liver disease:
- Eg: 1ry biliary cirrhosis
- Causes: ↑cholesterol
- Features:
o Accumulation of lipoprotein-X is the main causative factor
o No clear association with CHD
Mainly ↑TG
4. T2DM:
- Common; secondary to insulin resistance and hyperinsulinemia
- Causes: ↑TG, ↓HDL (mixed dyslipidaemia)
- Features:
o Lipoprotein abnormalities are related to the severity of the insulin resistance
o ↑TG results from: ↑ substrate availability (glucose, FFA), decreased lipolysis of VLDL
5. Drugs:
- Causes:
o Cyclosporin: ↑cholesterol
o Anabolic steroids: ↓HDL
o Others: ↑TG (mainly)
- BB, olanzapine, steroids, clozapine, interferons, thiazides
- Protease inhibitors: usually as part of lipodystrophy syndrome
6. Obesity:
- Causes: mixed changes ↑total cholesterol, ↑LDL/VLDL, ↑TG, ↓HDL (in 5%)
- Features:
o Loss of body fat can reverse the ↑TG and ↑cholesterol
Mainly ↓HDL
7. Smoking
- Causes: ↓HDL
- Features:
o Smoking associated with 0.1-0.2mmol/L decline in serum HDL
- Effects reversible within 1-2 months after smoking cessation
Comments on answers:
A. PI therapy: yes, mainly ↑TG
B. T2DM: yes, mainly mixed dyslipidaemia secondary to insulin resistance
C. Obesity: yes, mixed changes (in all)
D. Alcohol excess: ↑TG
The most common mechanism for malignant ascites is:
A. cardiac failure
B. hypoalbuminaemia
C. obstruction of abdominal lymphatics
D. portal hypertension
E. portal vein thrombosis
Answer C- obstruction of abdominal lymphatics
Ascites
- Cirrhosis: main cause of ascites (85%)
- Cancer: contributes or is the sole cause in ~7% of px
Malignancy related ascites:
- Malignant disease can cause ascites by (at least) 6 mechanisms:
Cause Frequency among patients with malignancy-related ascites
Peritoneal carcinomatosis 53 percent
Massive liver metastases causing portal hypertension 13 percent
Peritoneal carcinomatosis plus massive liver metastases 13 percent
Hepatocellular carcinoma plus cirrhosis 13 percent
Chylous ascites due to malignancy, usually lymphoma 7 percent
Budd-Chiari syndrome due to malignancy occluding the hepatic veins Rare
* N.B Peritoneal carcinomatosis: widespread metastatic deposits in the peritoneum
** Budd-Chiari: the clinical sx caused by occlusion of the hepatic veins abdo pain, ascites, hepatomegaly
Origin of 1ry can determine mechanism of ascities:
- Ovarian/Urinary bladder/Peritoneal mesothelioma peritoneal carcinomatosis
o blockage of draining lymphatic channels (and ↑vascular permeability)
- Colon/gastric/breast/pancreas/lung peritoneal caricnomatosis and large liver mets:
o Obstruction/compression portal veins OR
o Liver failure
- Lymphomas:
o Lymph node obstruction accumulation of chylous ascites
o Primary effusion lymphoma (a B-cell lymphoma due to HHV8): can involve serosal surface
symptomatic serous effusion (with high-grade malignant lymphocytes but no detectable mass lesion)
- Liver disease:
o Ascites in liver disease is usually due to HCC (rather than liver mets).
Risk factors for HCC-related ascites:
• Major:
o Chronic Hep B (acquired in infancy or childhood- esp Asia)
o Chronic Hep C
o Alcoholic cirrhosis (often compensated cirrhosis)
• Moderate: non-alcoholic fatty liver disease
o Ascites usually due to :
tumor volume replacing critical portion functional liver mass OR
tumour invading portal vein portal vein thrombosis
Serum-to-ascites albumin gradient (SAAG):
- Identifies portal hypertension (vs non-portal hypertension) causes of ascites
- SAAG >1.1g/dL (11g/L)= portal hypertension [like older ‘transudate’] {‘capillary hydrostatic pressure’}
o Mainly:
HCC complicating cirrhosis; massive liver mets [94% have SAAG >1.1g/dL]
Other causes:
• Heart failure; hepatic vein occlusion, constrictive pericarditis, kwashiorkor (protein deficiency)
o Correlating findings: [
Low protein (
- SAAG
o Mainly:
Peritoneal carcinomatosis in the absence of cirrhosis or massive liver mets (95%)
Other causes:
• Infection, pancreatitis/serositis, nephritic sx, hereditary angioedema
o Correlating findings:
High protein, high LDH, low glucose , ↑WCC, low pH
Comments on answers:
A. Cardiac failure:
- a cause of SAAG >1.1g/dL ascites, but not a cause of malignant ascites
B. Hypoalbuminaemia:
- ↓Albumin ↓ colloid osmotic pressure < hydrostatic pressure edema
- A secondary effect of a primary cause
C. Obstruction of abdo lymphatics:
- Usually due to peritoneal carcinomatosis, which accounts for 53% of malignancy-related ascites
D. Portal hypertension:
- Mainly due to HCC complicating cirrhosis or massive liver mets in this context; ~13%
E. Portal vein thrombosis:
- can cause malignancy-related ascites if tumour invades the portal vein (usually due to HCC)
Albumin comprises 75-80% of normal plasma colloid oncotic pressure and 50% of protein content. When plasma proteins, especially albumin, no longer sustain sufficient colloid osmotic pressure to counterbalance hydrostatic pressure, edema develops.
Which of the following is the primary mechanism of body iron regulation?
A. Shedding of duodenal enterocytes
B. Regulation of enterocyte surface expression of transferring receptor (TfR1)
C. Regulation of enterocyte ferritin content
D. Renal haemosiderin excretion
E. Alteration of Kuppfer cell iron metabolism gene expression
Answer A – Shedding of Duodenal Enterocytes
Summary of Iron Metabolism and Regulation:
- Absorption in the duodenum / jejunum
- Ferric Ferrous via ferric reductase at brush border
- Transported into enterocyte via DMT-1 (enhanced by vitamin C)
- Exported from enterocyte via ferroportin
- Ferrous Ferric via haphaestin
- Travels in blood stream with apotransferrin (ie. forms transferrin)
- Storage in liver, reticuloendothelial cels and bone marrow
- Iron loss in faeces and via bleeding losses
The main mechanism of iron regulation is via IRON ABSORPTION
-absorption must be carefully regulated since no physiological control over daily iron losses from the body
• Liver secretes hepcidin which acts on ferroportin
o Increased iron stores increased hepcidin inhibition of ferroportin (degradation)
o Iron deficiency decreased hepcidin increased ferroportin increased iron absorption
• Transferrin receptor is upregulated on all cell membranes in iron deficiency (notes solubule transferring receptor released into circulation by membrane proteases with transferring receptor not associated with transferring as occurs in iron deficiency)
Other options mentioned…
-iron that enters enterocytes and does not exit via ferroportin can remain bound to intracellular ferritin
-this ferritin usually remains in situ and will be lost from body when enterocyte sloughs
-more iron will remain bound to enterocyte ferritin when stimulated by hepcidin in order to limit Fe absorption
-Kupffer cells are macrophages which live in the liver and form part of the reticuloendothelial system
-play important role in recycling body iron (ingest aged RBCs and recycle Fe)
-haemosiderin accounts for 1/3 of all stored iron and is a non-soluble form (stains with Perl’s reaction)
Iron Absorption
In general, the digestive system is set up to maximize absorption; there is no regulation of the amounts of substances absorbed into the body. A notable exception is iron, in which daily dietary absorption is regulated so that it matches daily iron loss. The reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism to eliminate much iron from the body. Iron is a necessary component of various enzymes, but its major role is in oxygen-binding as a component of hemoglobin in red blood cells. Iron deficiency leads to anemia, a decrease in the oxygen carrying capacity of blood. However, too much iron in the body can be extremely toxic to tissues because it promotes the formation of free radicals.
The majority of the body’s iron is found in hemoglobin of developing and mature red blood cells. Of the remaining iron, a significant portion is stored in the liver, both in the hepatocytes, and in the Kupffer cells (also known as reticuloendothelial cells), a type of macrophage found in the liver. Kupffer cells play an important role in recycling body iron. They ingest aged red blood cells, liberating iron for reuse by breaking down hemoglobin.
The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron. The important players in the dietary absorption of iron are diagrammed in the figure. (Note that this is a simplified scheme; not all the details are included).
Iron is brought into the cell through an active transport process involving the protein DMT-1 (divalent metal transporter-1), which is expressed on the apical surface of enterocytes in the initial part of the duodenum. DMT-1 is not specific to iron, and can transport other metal ions such as zinc, copper, cobalt, manganese, cadmium or lead. Enterocytes also absorbe heme iron through a mechanism that has not yet been characterized.
Once inside the enterocyte, there are two fates for iron:
• It may leave the enterocyte and enter the body via the basolateral transporter known as ferroportin.
• It can be bound to ferritin, an intracellular iron-binding protein. For the most part, iron bound to ferritin in the enterocyte will remain there. This iron will be lost from the body when the enterocyte dies and is sloughed off from the tip of the villus.
Iron that enters the body from the basolateral surface of the enterocyte is rapidly bound to transferrin, an iron-binding protein of the blood. Transferrin delivers iron to red blood cell precursors, that take up iron bound to transferrin via receptor-mediated endocytosis.
Normally, the capacity of transferrin to bind iron in the plasma greatly exceeds the amount of circulating iron. The transferrin saturation (percent of transferrin occupied by iron) is measured to determine if an individual has an excessive load of iron in the body. The normal transferrin saturation is in the range of 20-45%.
________________________________________
Iron absorption by the enterocyte is programmed to match the body’s needs. There are two major signals that affect iron absorption.
1. One signal reflects the need for iron due to erythropoiesis (red blood cell generation). The hormone erythropoietin (produced by the kidneys) stimulates red blood cell production, but it is NOT the signal regulating iron absorption. Rather, once hematopoiesis is stimulated, another signal is generated that promotes increased iron absorption.
2. A second signal depends upon the amount of iron in body stores. Iron absorption is stimulated if the level in body stores is low.
These signals (and others) regulate iron absorption in the proximal duodenum, where iron is absorbed. An important player in this regulation is the recently discovered hormone hepcidin. Hepcidin is produced by hepatocytes when iron stores are full. Inflammation can also stimulate hepcidin production.
The figure shows the model for how hepcidin acts on duodenal enterocytes to decrease the amount of iron absorbed into the body. Experiments have shown that hepcidin binds to the basolateral iron transporter ferroportin. This causes ferroportin to be internalized and degraded. As a result, more iron remains within the enterocyte. This stimulates ferritin synthesis, so that the iron that enters the enterocyte gets bound to ferritin. This iron is lost from the body when the enterocyte dies.
A previously well 64-year-old man presents with GORD. He is on no current medications. Gastroscopy demonstrates Barrett’s oesphagus with erosive oesophagitis above the squamocolumnar junction. Random biopsies are reported as demonstrating dysplastic epithelium with features of active inflammation. The most appropriate next step in management is:
A. Endoscopic Ultrasound
B. CT chest/abdo
C. Repeat biopsies after two months of treatment with PPIs
D. Surgical resection
E. Surveillance endoscopy in one year
Answer B – Repeat biopsies after 2 months of treatment with PPIs
Summary of American Guidelines for Barrett’s Oesophagus Mx 2011:
In patients with multiple risk factors associated with esophageal adenocarcinoma (age 50 years or older, male sex, white race, chronic GERD, hiatal hernia, elevated body mass index, and intra-abdominal distribution of body fat), we suggest screening for Barrett’s esophagus (weak recommendation, moderate-quality evidence).
We recommend against screening the general population with GERD for Barrett’s esophagus (strong recommendation, low-quality evidence).
(Note Australian GESA guidelines for endoscopy indications 2008 include:
-dx unclear (because sy either non-specific or atypical for GORD)
-symptoms persist or are refractory to treatment
- alarm symptoms (symptoms sugget severe or complicated oesophagitis eg. haematemesis, dysphagia, wt loss)
-other diagnoses seem possible eg. infective or drug-induced oesphagitis, oesophageal malignancy, gastroduodenal disorders
The diagnosis of dysplasia in Barrett’s esophagus should be confirmed by at least one additional pathologist, preferably one who is an expert in esophageal histopathology (strong recommendation, moderate-quality evidence).
•Published rates of progression from low-grade dysplasia to either high-grade dysplasia or esophageal adenocarcinoma range from 0.5% to 13.4% per patient per year, depending on the rigor of pathologic confirmation of dysplasia. Quality of Evidence: Low
•A recent meta-analysis of multiple historical studies reported an overall risk of progression from high-grade dysplasia to cancer of 6% per patient per year. Quality of Evidence: Moderate
We suggest that endoscopic surveillance be performed in patients with Barrett’s esophagus (weak recommendation, moderate-quality evidence).
We suggest the following surveillance intervals (weak recommendation, low-quality evidence):
•No dysplasia: 3–5 years
•Low-grade dysplasia: 6–12 months
•High-grade dysplasia in the absence of eradication therapy: 3 months.
- For patients with Barrett’s esophagus, GERD therapy with medication effective to treat GERD symptoms and to heal reflux esophagitis is clearly indicated, as it is for patients without Barrett’s esophagus. Quality of Evidence: High
- Evidence to support use of acid-reducing agents, specifically PPIs, in patients with Barrett’s esophagus solely to reduce risk of progression to dysplasia or cancer is indirect and has not been proven in a long-term controlled trial. The risks and potential benefit of long-term PPI therapy should be discussed carefully with patients with Barrett’s esophagus in the context of their overall health status and medication use. Quality of Evidence: Low
- Evidence does not support greater than standard doses of PPI therapy with an expectation of cancer risk reduction. Quality of Evidence: Low
•Antireflux surgery is not more effective than medical GERD therapy for the prevention of cancer in Barrett’s esophagus. Quality of Evidence: Moderate
We recommend endoscopic eradication therapy with radiofrequency ablation (RFA), photodynamic therapy (PDT), or endoscopic mucosal resection (EMR) rather than surveillance for treatment of patients with confirmed high-grade dysplasia within Barrett’s esophagus (strong recommendation, moderate-quality evidence).
We recommend EMR for patients who have dysplasia in Barrett’s esophagus associated with a visible mucosal irregularity to determine the T stage of the neoplasia (strong recommendation, moderate-quality evidence).
•Most patients with high-grade dysplasia (70%–80%) can be successfully treated with endoscopic eradication therapy. Esophagectomy in patients with high-grade dysplasia is an alternative; however, current evidence suggests that there is less morbidity with ablative therapy. Quality of Evidence: Moderate
•Before proceeding with esophagectomy, patients with high-grade dysplasia or intramucosal carcinoma with Barrett’s esophagus should be referred for evaluation by surgical centers that specialize in the treatment of foregut cancers and high-grade dysplasia. Quality of Evidence: High
Case discussion:
- patient is male and >50
- symptomatic reflux symptoms not yet medically treated
- we are not told if dysplasia is low or high grade
- active oesophagitis on biopsy
Cirrhosis of the liver in genetic alpha-1-antitrypsin deficiency is most likely to be the result of which of the following?
A. Loss of inhibition of serum elastase.
B. Concomitant infection with hepatitis C.
C. Intracellular accumulation of alpha-1-antitrypsin.
D. Associated alcohol-induced fibrosis.
E. Hypoxia secondary to emphysema.
Answer C. Intracellular accumulation of alpha-1-antitrypsin.
Alpha-1 antitrypsin (AAT) is a serine protease inhibitor
• It is produced in the liver
• AAT deficiency is autosomal co-dominant inheritance of mutations in the alpha 1 antitrypsin gene
• AAT deficiency is associated with lung, liver and skin (rare) disease
• Lung disease is due to the loss of effect of the normal protein, while liver disease is due to impaired secretion of the abnormal protein.
A. Loss of inhibition of serum elastase.
This is the mechanism for lung damage/emphysema in AAT deficiency; an imbalance between neutrophil elastase in the lung, and the elastase inhibitor (AAT) resulting in tissue degradation.
B. Concomitant infection with hepatitis C.
“…alcohol use and viral hepatitis do not appear to increase the risk of progressive hepatic failure” UTD
another snippet from UTD…”Some investigators have also suggested that the PI*ZZ phenotype predisposes to hepatitis and that the liver damage is mediated by viral infection”….hmmmm.
C. Intracellular accumulation of alpha-1-antitrypsin.
Nyes….. Harrisons….
“ 1AT deficiency results from an inherited disorder that causes abnormal folding of the 1AT protein, resulting in failure of secretion of that protein from the liver. It is unknown how the retained protein leads to liver disease.”
UTD…”The pathogenesis of the liver injury in AAT deficiency differs from that of the pulmonary disease. The latter is primarily due to destruction of elastin by elastase, the activity of which is increased because of deficiency of the elastase inhibitor AAT. In contrast, liver disease is caused by pathologic polymerization of the variant AAT, resulting in intrahepatocyte accumulation of AAT molecules, rather than a proteolytic mechanism. Pathologically, the accumulated AAT appears as inclusions within hepatocytes that stain positively with periodic acid-Schiff (PAS) reagent but resist digestion by diastase”
D. Associated alcohol-induced fibrosis.
“…alcohol use and viral hepatitis do not appear to increase the risk of progressive hepatic failure” UTD
E. Hypoxia secondary to emphysema.
Wha—ah??
A bit more detail about AAT …
At least 100 alleles of AAT have been identified and given a letter code based on electrophoretic mobility …
• Normal – normal alleles are associated with normal levels of AAT and normal function. The family of normal alleles is referred to as M (the normal phenotype is MM)
• Deficient – deficient alleles are associated with plasma AAT levels
• Null – null alleles lead to no detectable AAT protein in the plasma – this is the least common phenotype and is the most severe form
Liver disease…
• has only been observed in some individuals with alleles causing intrahepatocyte accumulation
• has not been observed in null-null individuals, as there is no protein to accumulate (however highest proteolytic risk)
• intrahepatocyte accumulation of Z-type molecules occurs within the rough ER and results from abnormal folding and aggregation of variant AAT molecules in a mechanism called loop-sheet polymerization
o increased temperature and increased concentration of Z-type protein promote this
o drugs under development to inhibit this process
• as well as abnormal folding, there is also a second defect required; decreased degradation of Z-type molecules within the ER ?due to defects in proteosomal or autophagic degradation pathways which further promotes the intrahepatocyte accumulation of ATT
• the exact mechanism by which liver damage occurs is unclear
o ?simple cell engorgement due to mass build up
o ?release of lysosomal enzymes
• adults with at-risk alleles (Z and M) may develop adult onset cirrhosis or HCC (cirrhosis often can onset without antecedent childhood liver disease)
• HCC risk is greater in men than women
• Obesity may also be a risk factor
• In contrast, alcohol use and viral hepatitis do not appear to increase the risk of progressive hepatic failure
Skin disease….
Although rare, the major dermatologic manifestation of AAT deficiency is necrotizing panniculitis
• Inflammatory lesions of skin and subcutaneous tissue
• Mean age of onset 40 yo
• p/w/ one or more hot, painful reg nodules or plaques on the thigh or buttocks
• RARE!!! Less than 50 cases reported in the English literature…
Other associations…proposed but not established…
• Vascular disease; inflammatory bowel disease, GN and vasculitis….
A 45-year-old woman has a history of terminal ileal Crohn’s disease for which she had a terminal ileal resection eight years ago. Surgery was complicated by small bowel leak post operatively, requiring laparotomy and prolonged drainage with bowel rest (total parenteral nutrition). Following recovery she remained well until two weeks ago, when she presented with two episodes of abdominal pain, bloating and vomiting which lasted two to three hours each and then resolved. There has been no change in bowel habit and no fever. She is on no medication.
Examination reveals mild tenderness in the lower abdomen. Bowel sounds are normal.
A computed tomography (CT) scan is performed and representative slices are shown below.
Which of the following is the most likely cause for her current symptoms?
A. Adhesions.
B. Recurrence of Crohn’s disease.
C. Psoas abscess.
D. Colonic carcinoma.
E. Irritable bowel syndrome.
Answer B. Recurrence of Crohn’s disease.
The role of CT in the evaluation of Crohn’s is well accepted….
- to depict bowel involvement
a. bowel thickening (luminal thickening 5-15mm), usually distal small bowel
b. can be anywhere along the GIT - to show extraluminal pathology e.g. abscess, obstruction, fistula
CT should be the first radiologic procedure performed in patients with acute symptoms and suspected or known Crohn’s disease; the ability to demonstrate bowel wasll, adjacent abdominal organs, mesentery and retroperitoneum makes CT superior to barium studies in diagnosis the complications of Crohn’s (bowel wall thickening, mesenteric oedema, lymphadenopathy, abscess/phlegmon formation. While barium is more sensitive for detecting fissures and fistulae, CT is superior in demonstrating the sequelae i.e. air in the urinary bladder in enterovesical fistula. One limitation of CT has been delineating active vs. inactive disease; mesenteric standing can remain during remission.
A 30yr old woman presents 3 months post-partum with weight loss, tremor, palpitation, and heat intolerance. On clinical examination, she is tachycardic, has a fine tremor, lid retraction, lid lag but no goitre.
Thyroid function test tresults are:
- fT4 35pmol/L [10-24]’
- fT3 12.0 pmol/L [3.8-6.8]
- TSH
Thryoid scintiscan is below:
Which of the following is the most likely cause of the thyrotoxicosis?
A. Factitious thyrotoxicosis
B. Postpartum thyroiditis
C. Graves disease
D. Subacute thyroiditis
E. Iodine-induced thyrotoxicosis
Answer B- Postpartum thryoiditis
From stem:
- Clinically: signs of hyperthyroidism 3 months post-partum
- Biochemically: elevated fT4 and fT3, suppressed TSH hyperthyroidism
- Thyroid RAI scan: v small area of uptake
Postpartum thyroiditis
Pathogenesis:
- destructive thyroiditis induced by autoimmune mechanism, within 1 yr after parturition (can also occur after spontaneous or induced abortion), often associated with anti-TPO ab
o Considered a variant form of chronic Hashimoto’s
- “very common and under-recognised”:
o 5% of women
o higher rates if: previous PPT, T1DM, +ve TPO-ab (30-50% of the ~10% of women who have TPO ab)
Presentation:
- Transient hyperthyroidism alone (peaks 1-6/12 post partum)
- Transient hypothyroidism alone (peaks at 9/12 post partum)
- OR Transient hyperthyroidism, followed by hypothyroidism, then recovery (most commonly, following pathogenesis)
Natural progression:
- Most recover and are euthyroid within 1 year postpartum
o 25% develop permanent hypothyroidism TSH needs to be checked every 3/12 in the first 1 year
- Recurrent postpartum thyroiditis occurs in up to 80% of subsequent pregnancies
Diagnosis:
- Clinical manifestations:
o Can be identical to painless thyroiditis
o 20-30%: Hyperthyroid symptoms (1-4months post delivery), then hypothyroidism (for 2weeks to 6months duration), then recovery
o + nontender goitre
- TFTs:
o ↓TSH, ↑ or high-normal fT4 and fT3 (in hyperthyroid phase)
o ↑TSH, ↓fT4 or low normal (in hypothyroid phase)
o CRP/ESR: mildly elevated
o Anti-TPO ab: not routinely measured in all
o TSI (thyroid stimulating immunoglobulins): can be measured to differentiate from Graves’ (↑ in Graves’)
- RAI/thyroid scintiscan:
o Mainly to differentiate from Graves’ disease
Graves’: high uptake values
PPT: low RAI uptake (usually
o N.B pregnancy and breastfeeding are absolute contraindications
Differentiating from Graves’
- Graves can also begin in the postpartum period (recurrent or new-onset)
o BUT PPT is ~20x more likely than an initial episode of postpartum Graves’
- Main clinical differences:
o PPT: usually mild hyperthyroidism (clinically and biochemically), minimal thyroid enlargement, no Graves’ ophthalmopathy
Usually transient
TFTs: fT4 is elevated to a greater degree than T3
TSI: not elevated
RAI: low uptake, decreased vascularity on U/S
o Graves’: more symptomatic, higher serum thyroid hormones, more enlargement, ophthalmopathy or pretibial myxedema,
Progresses/gets worse or doesn’t change (but doesn’t remit)
TFTs: T3 is elevated to a greater degree than fT4
TSI: elevated
RAI: high uptake, hypervascularity on U/S
Screening and prevention issues:
- Screening not indicated
- If high risk (T1DM, previous hx, anti-TPO ab): serum TSH at 3 and 6/12 postpartum (+ fT4 and fT3 if TSH low)
- No established therapies of prevention
Treatment:
- No RCTs done, based on observational studies/clinical experience
- Asymptomatic women: (with mildly elevated TSH)
o no intervention necessary
o TFTs remeasured in 4-8/52, if >10, probably should replace T4
- Hypothyroid symptoms: (and elevated TSH)
o should be treated with thyroxine (T4) and periodically monitored
- Hyperthyroid symptoms:
o 40-120mg propranolol (esp if breastfeeding) or 25-50mg atenolol daily until serum T3 and fT4 normalise
o RAI and antithyroid drugs are of no value because the synthesis of T4 and T3 is decreased anyway
- Duration of treatment controversial, try and wean after 6-12/12
o Monitor at 6-8/52, then 3/12, 6/12
- If recovered: measure TSH levels annually (esp within 5-10yrs after diagnosis)
Comments on answers:
A. Factitious thyrotoxicosis: no, symptomatic
B. Postpartum thyroiditis
C. Graves disease:
a. Symptoms consistent, but maybe on the milder side than true Graves’
b. No specific Graves’ ophthalmopathy: periorbital oedema, proptosis
i. N.B lid lag is due to contraction of the levator papebrae muscles of eyelid can give appearance of proptosis (“apparent proptosis”); lid retraction secondary to thyroid hormone excess
ii. These features alone do not indicate the presence of ophthalmopathy
c. RAI not consistent with diffuse/high uptake in Graves’
D. Subacute thyroiditis: uncommon cause of hyperthyroidism
a. De-Quervain’s thyroiditis (subacute granulomatous thyroiditis):
i. W>M, presents young-middle aged (incidence decreases with age)
ii. Cause: usually viral (coxsackie, mumps, adeno), can be preceded by URTI. Can develop post-partum as well
iii. Symptoms of both hyper and hypothyroidism, with neck pain and fever + dysphagia (painful)
iv. RAI: decreased uptake (cf Graves’)
v. Usually self-limited, symptomatic treatment with beta-blockers + NSAIDs
E. Iodine-induced thyrotoxicosis:
a. Can happen but no real need to think this here
In patients with untreated post-transfusion hepatitis C, the lifetime risk of progression to cirrhosis best approximates:
A. 1%.
B. 5%.
C. 20%.
D. 50%.
E. 80%
Answer C. 20%
Most patients infected with HCV in the US/Europe acquire the disease through IV drug use or blood transfusion; transfusion related HCV is extremely rare now since routine testing of the blood supply in ?early 1990s (initially antibodies and ALT, now ?PRC testing) Rates of endemic disease are higher in other parts of the world). Risk factors include (in decreasing degree of risk) – IVDU, blood transfusion, sex with an IVDU, jail >3 days (??!!), religious scarification, stuck/cut with bloody object, pierced ears/body parts, Ig injection). HCV has also been associated with intranasal cocaine use, presumably due to blood on shared straws. * 1983-1990 based on non-A, non-B hepatitis.
Clinical features and natural history of HCV infection
• HCV can present with both acute or chronic hepatits, however the acute infection is often asymptomatic, and if symptoms are present they usually abate within a few weeks. Acute infection rarely causes hepatic failure
• However, acute infection usually leads to chronic infection, with 60-80% of cases developing chronic hepatitis, which is usually slowly progressive and may not result in clinically apparent liver disease until later in life.
• Approximately 20-30% of chronically infected individuals develop cirrhosis over a 20-30 year period of time
• HCV is the most common cause of chronic liver disease, and the most frequent indication for liver transplantation in the US
Choose your own adventure…
- go and read about HCV on your own
- keep reading and look at my HCV notes
Hepatitis C Virus
• causes ~20% of acute hepatitis in the US, often the presence of HCV RNA in the serum or liver is the first biochemical evidence of HCV infection (detecable by PCR within days to eight weeks of exposure. Serum aminotransferases become elevated approximately 6-12 weeks after exposure, though this is highly variable (1-26 weeks)
• acute infection is either asymptomatic, or mild (jaundice in less than 25%), so need to suspect in at risk patients with non specific symptoms (malaise, nausea, mild RUQ pain). Duration 2-12 weeks. Fulminant hepatic failure due to HCV is rare, but may be more common in patients with underlying chronic HBV
• the risk of chronic infection after an acute episode of HCV is high (60-80% have persistently elevated liver enzymes, while 80-100% remain HCV RNA positive). The rate of spontaneous clearance of virus after is has persisted for at least 6/12 is low. The reason for the high prevalence of chronic infection is unclear ?genetic diversity of the virus ?tendency towards rapid mutation and so improved immune avoidance. Host factors may also be involved ?HLA types. The amount of inoculated virus is thought not to be a risk factor.
• chronic infection is often asymptomatic, or mild non-specific symptoms (nausea, anorexia, myalgia, weakness and weight loss)
• symptoms do not reliably reflect disease activity, although symptoms seem to be more common once cirrhosis develops
• HCV infection has been associated with cognitive impairment, independent of the severity of liver disease (mechanism unclear)
• Serum transaminases vary widely between individuals and among individuals with HCV infection over time. May have a normal serum ALT!! It is unusual to have elevations of more than 10x normal. In the majority of patients, only slight enzyme elevations are seen. ALT levels correlate poorly with histology (unless ALT increased greater than 10x). ALT is not useful as a marker of response to therapy (may have histological improvement with interferon without normalizing ALT)
• Despite this, the levels of AST to ALT is still looked at… AST>ALT has high specificity for cirrhosis (????)
Natural history…
• Hard to define because of the long course of the disease. Approximately 20-30% of chronically infected individuals develop cirrhosis over a 20-30 year period of time. Some patients show no evidence of cirrhosis for at least 50 years.
• May not have increased all-cause mortality (if follow up less than 25 years) but increased liver related mortality.
• Mortality in patients with HCV is not always related to liver disease; a population based study from Australia found that most deaths in young patients with HCV were due to continued drug use rather than from infection
• The reason for differences in the susceptibility to disease progression among individual patients is incompletely understood
• Cirrhosis
o The development of cirrhosis is silent in the majority of patients; may have no clinical symptoms or signs, though generally tend to be more symptomatic. Elevated serum bilirubin, hypoalbuminaemia or decreased platelets may be suggestive of cirrhosis
o Serum alpha fetoprotein may be elevated in HCV infection and does not necessarily imply the presence of hepatocellular carcinoma or cirrhosis. However an elevated aFP should prompt imaging to result out HCC. Serial testing may also be warranted.
• Decompensation
o Cirrhosis is a prerequisite for most of the major complications
o Usually ascites, followed by variceal bleeding, encephalopathy and jaundice
• Hepatocellular carcinoma
o Death is usually due to ESLD rather than HCC, however HCV accounts for ~1/3 of HCC cases (US data)
o Estimates of risk of developing HCC varies from 0-3% per year, and greater risk seems to be associated with particular genotypes (1b>2a/c)
o In contrast to HBV, HCC in HCV occurs almost exclusively in those with cirrhosis
• Survival
o Compensated cirrhosis
3 year survival 96%
5 year survival 91%
10 year survival 79%
o once decompensated cirrhosis has occurred, 5 year survival falls to 50%
o survival overall may be worse in patients who develop cryoglobulinaemia
o causes of death varies with age group and demographic i.e. higher rates of ‘unnatural death’ amongst IVDU, those with mental health disorders etc
o alcohol promotes the progression of chronic HCV, even with relatively low EOTH intake (increased HCV replication and has been linked with accelerated patterns of liver injury)
Viral factors
The effect of viral factors on disease progression is less certain – date relating to viral genotype and quasispecies in predicting outcome are too contradictory to reach definitive conclusions….however;
1. genotype 1b is overrepresented among patients with cirrhosis and those with HCC, though other studies have found no association after adjusting for disease duration or age (? Patients with genotype 1b have had it for longer therefore high incidence of HCC and cirrhosis)
2. disease progression may be accelerated in patients who are infected by more than one HCV infection (?synergistic effect of coinfection)
3. co-infection with HBC/HCV may result in more rapid disease progression – note: some patients with HCB and HCV may lack serological markers of HBC infection ?reason unknown. May not show HBsAg though HBV DNA positive
the best clinical predicator of disease in HCV is the amount of inflammation and fibrosis on liver biopsy
Extrahepatic manifestations of HCV
• haematological – mixed cyroglobulinaemia and lymphoma
• renal - esp membranoproliferative GN
• autoimmune - thyroiditis, coexisting autoimmune hepatitis
• dermatologtical – porphyria cutanea tarda, lichen planus
• DM
.
Which of the following features in a patient with colon cancer is most suggestive of hereditary nonpolyposis colon cancer (HNPCC)?
A. Right-sided lesion
B. Microsatellite instability in the tumour tissue
C. Multiple synchronous polyps
D. Brother with colon cancer at age 55
E. Uncle with a germline MLH1 mutation
Answer Answer Quoted as C!!! Isn’t C correct for FAP? I would have to say B!
HNPCC
-autosomal dominant trait
-approximate 80% lifetime risk for colon cancer
-associated germline mutations of several mismatch repair (MMR) genes
- hMSH2 on chr 2 and hMLH1 on chr 3 account for 95%
-mutations lead to…
errors in DNA replication
defective DNA mismatch repair
(microsatellite instability)
-accounts for 2-3% of all CRC
-associated with an unusually high frequency of cancer arising in the proximal large bowel (ie ‘R-sided’)
-median age for cancer appearance
-also associated with increased risk of ovarian, endometrial, gastric cancers etc.
- can identify HPNCC via
1. Amsterdam Criteria: identifies high-risk patients for molecular genetic testing: - 3 or more relatives with histologically defined colorectal cancer
- one of whom is a first-degree relative of the other two (ie. parent, child, sibling)
- one or more cases diagnosed before age 50
- CRC involving at least 2 generations
- FAB excluded
2. Genetic Testing - immunohistochemical staining for DNA mismatch repair gene expression + microsatellite instability testing (latter is a surrogate marker for DNA mismatch repair gene dysfunction) performed first
- molecular analysis of DNA (genetic testing for mutations in DNA MMR genes) – expensive and time consuming
A 55-year-old woman with a long history of constipation-predominant irritable bowel syndrome presents for review. She complains of worsening constipation and increased bloating. She had a normal colonoscopy at the age of 40 years. She presented to the emergency department six days ago with abdominal bloating which subsided following an enema. An abdominal X-ray is shown below.
The most appropriate next step is to:
A. increase fibre intake.
B. add a laxative to her regimen.
C. perform a colonoscopy.
D. perform an abdominal computed tomography (CT) scan.
E. perform an upper abdominal ultrasound.
Answer C. perform a colonoscopy.
Diarrhoea predominant IBS
Stool cultues if Giardia is possible
Celiac disease screening
24 hour stool collection if osmotic or secretory diarrhoea is suspected, or a malabsorption syndrome
consider colonoscopy
Constipation predominant IBS
XR to exclude constipation
Lexible sigmoidoscopy/colonscopy should be performed in patients who are older than 50 because of the increased risk of CRC in this group
A 75-year-old man presents with progressive dysphagia. He is currently only able to ‘keep down’ liquids. He has lost 7 kg in weight over the last six weeks. Endoscopy shows a mass lesion in the distal oesophagus which does not allow passage of the endoscope into the stomach. Biopsies show adenocarcinoma. A computed tomography (CT) scan reveals thickening in the distal oesophagus as well as two liver lesions which prove to be metastatic on biopsy.
Which of the following is most appropriate to give him immediate and long lasting (>6 months) relief from dysphagia?
A. Oesophageal dilation.
B. External beam radiotherapy.
C. Percutaneous endoscopic gastrostomy (PEG) tube.
D. Self-expanding metal stent placement.
E. Ivor-Lewis procedure (distal oesophagectomy).
Answer D. Self-expanding metal stent placement.
Discussion
• Oesphageal dilatation doesn’t last long…
• External beam radioatherapy can create stricutres, also immediate-short term can make symptoms worse
• PEG tube just bypasses it….so I reckon it would help with dysphagia, but ultimately the patient will be unable to manage his own secretions, so I spose it wont help
• Stent, apparently is good.
• Ivor lewis gastrectomy (above) is unlikey to have immediate relief, and is often associated with ongoing reflux symptoms, though not usually dysphagaia
A 22yr old male presents with his 4th episode of pancreatitis. A CT scan of the pancreas is shown above. He has 2 1st degree relatives with chronic pancreatitis. There is no other significant family history. The most likely explanation for his episodes is:
A. Cystic fibrosis
B. Alcoholic pancreatitis
C. Hyperparathyroidism
D. Hereditary pancreatitis
E. Haemochromatosis
Answer D- Hereditary pancreatitis
From the stem:
- Clinical: 4th episode of pancreatitis, nil other hx
o No past hx; FHx: 2x 1st degree relatives with chronic pancreatitis
- CT: ? scattered pancreatic calcification
- Impression: could be acute relapsing pancreatitis, but CT is suggestive of chronic process
Chronic pancreatitis (exocrine pancreatic insufficiency)
Presentation:
- Episodes of acute inflammation (in a previously injured pancreas) OR
- Chronic damage with persistent pain/ or malabsotprion
Diagnosis:
- Classic triad (33%): pancreatic calcification, steatorrhea, diabetes mellitus
- Secretin stimulation test: [secretin stimulates pancreas to produce water and electrolytes]
o Abnormal results= >60% exocrine function lost
- Lab:
o Serum amylase and lipase often not elevated
o ↑bilirubin, ALP[may indicate cholestasis 20 to chronic inflame around CBD]; impaired glucose tolerance, ↑fasting BSL.
o ↓Serum trypsinogen (
D-xylose: a simple 5-carbon sugar (aldopentose monosaccharide) that does not require intraluminal digestion (from pancreatic enzymes)
Causes:
- Similar to that of acute pancreatitis (except*):
o Alcohol (most common cause in adults)
CF (most common cause in Children)
o * Idiopathic (25%; most common cause of non-alcoholic pancreatitis)
15% have a genetic basis:
• CFTR mutations [↑risk by 40-fold with 2 abnormal copies]; PSTI (trypsin inhibitor gene) mutations [↑risk by 14-fold]
• ↑risk by 600-fold by having both mutation
Severe protein-calorie malnutrition [‘tropical pancreatitis’, seen in Africa, Asia]
o ?Autoimmune chronic pancreatitis:
Seen increasingly in Japan, Italy; associated with ↑serum IgG and other autoimmune disorders (eg primary biliary cirrhosis, IBD etc). Rx: glucocorticoids
o Other: (relatively uncommon causes of pancreatic exocrine insufficiency)
↑triglycerides, neoplasms (panc, duodenum), Hereditary pancreatitis, Traumatic, Haemochromatosis, 1ry sclerosing cholangitis, 1ry biliary cirrhosis, Schwachman’s syndrome (pancreatic insuff and bone marrow dysfunction), ↓trypsinogen, ↓enterokinase, isolated ↓amylase/lipase/proteases, ↓1-antitrypsin
o *N.B Gallstones predominantly cause acute pancreatitis or relapsing-acute
Clinical:
- Persistent abdo pain + steatorrhea
o ~15%: steatorrhea only (no pain)
o Pain: continuous, intermittent or absent (pathogenesis poorly understood)
- Extensive destruction of pancreas (
o Steatorrhea and azotorrhea
- Other suggestive features:
o Weight loss, malabsoption signs/sx
Radiology:
- Hallmark: scattered pancreatic calcification (CT)
o Dynamic process that is incompletely understood- disappears in 33% of px with severe chronic pancreatitis
o Found in chronic pancreatitis due to:
Alcohol (most commonly)
Also: Hereditary, post-traumatic, severe protein-calorie malnutrition, hyperparathyroid, islet cell tumors, idiopathic chronic pancreatitis.
- Other modes: sonography, ERCP, endoscopic ultrasound (latter 2 provide info re: main pancreatic duct and smaller ducts)
o ERCP can also reveal pseudocyst missed by sonography or CT
Complications:
- Cobalamin (vit b12) malabsorption: 40% px with alcohol-induced CP, ~100% with CF induced CP
- Impaired glucose tolerance: but DKA is uncommon unless concomitant T2DM
- Nondiabetic retinopathy: 20 to vitamin A + zinc deficiency
- Effusions (with amylase): pleural, pericardial, peritoneal
- GI bleed: due to various causes (pseduocyst eroding duodenum, peptic ulceration, gastritis etc)
- Icterus: compression of CBD cholangitis biliary cirrhosis
- Pancreatic carcinoma: increased in px with CP for
