Hepatology

Question 1

NAFLD

Answer 1

NAFLD (overview):

• Description: A spectrum of disease characterized by hepatic steatosis in the absence of excessive alcohol consumption. May progress to cirrhosis. Most patients are diagnosed with NAFLD in their 40s or 50s
• pathophys of hepatic steatosis:
  (1) : reduced synthesis or secretion of very low-density lipoprotein (VLDL) from protein malnutrition or abetalipoproteinemia; or impaired beta-oxidation of free fatty acids (FFA)
  (2) leads to diminished hepatic export of FFA and increased importation of FFA from adipose tissue (esp with obesity, overfeeding, or the use of TPN)
  (4) leads to excessive accumulation of toxic lipids in the liver, including triglycerides, free fatty acids (FFA), ceramides, and free cholesterol.
  (5) FFAs are inducers of microsomal lipoxygenases, capable of producing hepatotoxic free oxygen radical species, hepatocellular injury, and fibrosis
  (6) Increased hepatic iron may also have a role in the development of NASH. Increased parenchymal hepatic iron concentration in NASH appears to correlate with the severity of fibrosis. It may be related to the generation of free oxygen radical species.
  (7) Leptin may contribute to the development of fibrosis in NASH. Leptin is a peptide produced primarily in adipose tissue. Leptin induces dephosphorylation of insulin-receptor substrate 1, rendering hepatocytes more insulin-resistant.
  (8) low serum adiponectin levels correlated with the presence of NAFLD, hepatic fibrosis, and the severity of the metabolic syndrome. Adiponectin is a hormone secreted exclusively by adipose tissue that produces beneficial effects on lipid metabolism, enhancing both lipid clearance from plasma and beta-oxidation of fatty acids in muscle
  (9) Perisinusoidal (zone 3) fibrosis in patients with NASH is primarily a consequence of the chronic inflammatory process with activation of lobular stellate cells.
• Associated with: Obesity, Systemic hypertension, Dyslipidemia, Insulin resistance or overt diabetes
• differential diagnoses: CLD secondary to alcohol, starvation, medication use (MTX, tamoxifen, amiodarone, valproate, anteretroviral for HIV), pregnancy related hepatic steatosis, viral hepatitis (A, B, C), auto-immune hepatitis, haemochromatosis. Also consider wilson’s disease, thyroid disorders, coeliac’s, alpha-1 antitrypsin def^y, HELLP, budd-chiari, drug-induced
• Features: hepatomegaly (liver span >18cm), signs of CLD (palmar erythema, spider nevi, ascites)
• LFTs:
  (1) elevated AST, ALT (they are 2-5 x higher than upper limit of normal).
  (2) AST : ALT ratio <1. Note, the degree of aminotransferase (AST, ALT) elevation does not predict the degree of hepatic inflammation.
  (3) elevated ALP, 2-3 x upper normal limit
  (4) normal bili and albumin, unless patient has cirrhosis
• Other labs: Elevated ferritin (>1.5 x upper limit is associated with NASH) or transferrin sats. Should also check Hep A, B, C serology, serum immunoglobulins, ANA, anti-SM antibody, anti LKM-1 (liver kidney microsomal antibody-1)
• liver USS: hepatomegaly, increased echogenicity (hyperechoic due to fatty infiltration)
• Fibroscan (Vibration controlled transient elastography): used to grade fibrosis based on liver stiffness
• CT - decreased hepatic attenuation; MRI - increased fat signal. CT/MRI are not usually required.
• liver biopsy is required if the pt is at high risk for advanced fibrosis (diabetes, obesity, >45yo, ferritin >1.5 x upper limit, stigmata of CLD suggestive of cirrhosis) or if the diagnosis is uncertain. Biopsy will confirm diagnosis + assess degree of injury

Histological criteria for NAFLD is >5% steatotic hepatocytes. May also have hepatic iron deposition

• NAFLD Activity score (NAS): used to grade disease activity in patients with NAFLD. Higher scores (5-8) largely diagnostic for NASH. The NAS is the sum of the biopsy’s individual scores for steatosis (0 to 3), lobular inflammation (0 to 3), hepatocellular ballooning (0 to 2).

NAFL

• simple hepatic steatosis present without evidence of inflammation
• Histology:
  (1) Steatosis alone.
  (2) Steatosis with lobular or portal inflammation, without hepatocyte ballooning.
  (3) Steatosis with hepatocyte ballooning but without inflammation

NASH (nonalcoholic steatohepatitis):

• Description: hepatic steatosis associated with lobular inflammation and apoptosis that can lead to fibrosis and cirrhosis
• Monitoring for cirrhosis: Fibroscan + serum fibrosis markers every 3years if ALT or AST elevated; every 4yrs if ALT and ALT normal. May progress to cirrhosis in up to 20 percent of patients
• Histology of NASH: requires the presence of hepatic steatosis in association with hepatocyte ballooning degeneration and hepatic lobular inflammation (typically in acinar zone 3). Fibrosis may be seen but is not a required diagnostic feature.

Additional findings: Apoptotic (acidophil) bodies; Mild chronic portal inflammation; Perisinusoidal collagen deposition that may result in zone 3 accentuation in a “chicken wire” pattern; Portal fibrosis without perisinusoidal or pericellular fibrosis; Cirrhosis, which is typically macronodular or mixed; Mallory-Denk bodies; Megamitochondria; Glycogenated (vacuolated) nuclei in periportal hepatocytes (rarely seen in alcoholic steatohepatitis); Lobular lipogranulomas; PAS-diastase-resistant Kupffer cells; Hepatic siderosis (typically mild) involving periportal hepatocytes or panacinar reticuloendothelial cells

• Grading/staging steatosis:
  (1) mild steatosis predominantly macrovesicular, involving up to 66% of biopsy; may see occasional ballooned zone 3 hepatocytes; scattered intra-acinar polymorphonuclear cells, intra-acinar lymphocytes; no or mild portal chronic inflammation.
  (2) moderate steatosis of any degree; ballooning of hepatocytes (predominantly zone 3) obvious; intra-acinar polymorphonuclear cells noted, may be associated with zone 3 pericellular fibrosis; portal and intra-acinar chronic inflammation noted, mild to moderate
  (3) severe panacinar steatosis; ballooning and disarray obvious, predominantly in zone 3; intra-acinar inflammation noted as scattered polymorphonuclear cells, ballooned hepatocytes, mild chronic inflammation; portal chronic inflammation mild or moderate

Fibrosis:

Staging fibrosis:

(F1) fibrosis stage 1: Zone 3 perisinusoidal fibrosis; focally or extensively present

(F2) Fibrosis stage 2: Zone 3 perisinusoidal fibrosis with portal fibrosis. Advanced fibrosis is F2 or greater.

(F3) Fibrosis stage 3: Zone 3 perisinusoidal fibrosis and portal fibrosis with bridging fibrosis

(F4) Fibrosis stage 4: Cirrhosis

Risk factors for advanced fibrosis:

• EtOH, BMI >28, DM, age >50
• biopsy proved liver inflammation, ballooning degeneration and mallory hyaline or evidence of fibrosis on biopsy.
• ALT and AST >or= 2 x upper limit normal

Criteria to refer to hepatologist:

• ALT and AST elevated despite 5-7% loss body weight
• features of advanced CLD (ascites, splenomegaly, jaundice)
• Steatohepatitis on liver biopsy
• Advanced fibrosis (fibrosis stage ≥F3)

Management of NAFLD

• Abstain from alcohol. As well as avoid heavy alcohol use (in men avoid >14 drinks/week or >4 drinks/day ;for women avoid >7 drinks/week or >3 drinks/day)
• Immunizations: hepatitis A virus and hepatitis B virus (Twinrix); pneumococcal vaccination; Boostrix (dTpa)
• Cardiovascular risk factors - optimise hypertension, hyperlipidemia (statin), glycemic control, weight loss 5-7% body weight (diet modification and exercise program) and referral for bariatric surgery after 6mo if weight loss goal not met. Pharmacological therapies inc insulin sensitizers, vitamin E (high dose 800IU/day) for patients with NASH. Fish oil supplementation. Daily aspirin.
• HCC surveillance: recommended for patients with NASH-related cirrhosis. The risk of HCC-related mortality is low in the absence of cirrhosis.

Mortality:

• Cardiovascular disease is the most common cause of death among patients with NAFLD

Question 2

Alcoholic fatty liver disease

Answer 2

Alcoholic liver disease should be suspected in patients with a history of significant alcohol consumption who present with AST > ALT, hepatomegaly, imaging/biopsy showing steatosis or cirrhosis.

Alcohol consumption:

As per UpToDate, alcohol consumption >100g EtOH per day (7-10 standard drinks) is associated with alcoholic hepatitis.

Significant alcohol consumption is defined as an average consumption of >210grams/wk (>15 s.d.) in men and >140grams/week (>10 s.d.) in women over a 2year period (united states standard drinks scale). Some sources state >21 standard drinks per week in men or >14 standard drinks per week in women over at least a two-year period (this probly comes from a different scale).

Excessive alcohol consumption is associated with alcoholic fatty liver disease (with or without steatohepatitis), alcoholic hepatitis, and cirrhosis.

Patients with an alcohol intake of >or=30 grams per day (one s.d. contains 14 grams of alcohol) are at increased risk of cirrhosis.

Hepatic steatosis:

• Hepatic steatosis is seen in approximately 90% of heavy drinkers and is typically macrovesicular. It may be seen within 2 weeks of regular alcohol ingestion and resolves rapidly with abstinence
• Patients with simple steatosis are often asymptomatic
• may have a normal examination or hepatomegaly.

Alcoholic hepatitis:

• patients with alcoholic hepatitis typically present with jaundice

Decompensated alcoholic cirrhosis:

• patients who have developed cirrhosis may have peripheral stigmata of liver disease (eg, spider angiomata, palmar erythema, gynecomastia, caput medusa, dupuytren’s, peripheral neuropathy, hepatosplenomegaly, testicular atrophy, digital clubbing)
• OR signs of hepatic decompensation (jaundice, weakness, peripheral edema, abdominal distension / ascites, or symptoms of gastrointestinal bleeding, such as hematemesis or melena, hepatic encephalopathy)

Labs:

• Moderate elevations of the AST and ALT (typically less than 300 int. unit/L, rarely higher than 500 int. unit/L. AST is typically < 8 x upper limit; ALT < 5 x upper limit)
• AST : ALT greater than or equal to 2. If the ratio is greater than 3, the percentage increases to 96% (as opposed to NAFLD it is typically <1)
• elevated serum bilirubin, GGT, elevated INR
• macrocytosis (high MCV), leukocytosis with a predominance of neutrophils

imaging:

• Liver imaging may provide evidence of hepatic steatosis or cirrhosis. Increased parenchymal echogenicity is a reliable criterion for diagnosing fatty liver.
• USS can exclude biliary obstruction, hepatic masses

Liver biopsy

• may be required if the diagnosis remains uncertain

DDx:

• should rule out Hep B, Hep C, haemochromotosis (test ferritin and transferrin sats), autoimmune hepatitis (test total IgG, ANA, anti-smooth muscle antibodies, anti-LKM1 antibodies).

Predictors of alcoholic liver disease:

• ANI: alcoholic liver disease to NAFLD index (ANI) is a model that has been developed to predict the probability that steatohepatitis is due to alcoholic liver disease. An ANI > zero favors a diagnosis of alcoholic liver disease, whereas an ANI < zero favors a diagnosis of NAFLD. It is based on a patient’s LFTs, MCV, BMI

■ High MCV (mean corpuscular volume);

■ High AST/ALT ratio;

■ Low body mass index;

■ Male gender

Question 3

Auto-immune hepatitis

Answer 3

Description:

• chronic, inflammatory liver disease

Epi:

• predominantly in women (moreso type 2 than type 1 AIH). Ratio is 4:1 F to M ratio in type 1, 10: 1 F to M ratio in type 2. Affects any age or ethnicity.

Pathophys:

• caused by an environmental trigger in a genetically predisposed individual
• hypothesised to involve the autoantigen, the major histocompatibility complex, and the T-cell receptor

Clinical features:

• wide spectrum of presentation (mild to severe symptoms), can be asymptomatic
• CLD / cirrhosis / decompesated liver failure (jaundice, ascites, splenomegaly)
• Nonspecific symptoms inc fatigue, anorexia, nausea, abdominal pain, itching. Arthralgia of small joints or a transient erythematous rash (rashes are seen in 8-17% of patients and most commonly appear as a transient nonspecific maculopapular rash, over the face, trunk, and upper arms)

Associated conditions:

• autoimmune thyroiditis, rheumatoid arthritis, type 1 diabetes mellitus, ulcerative colitis, celiac disease, and systemic lupus erythematosus, primary amenorrhoea

Labs:

• elevated AST and/or ALT (total numbers are >2 x upper limit), with AST:ALT <1.5. Aminotransferases may exceed 10-20* the ULN in acute presentations. Ratio of ALP to AST (or ALT) is typically less than 1:5.
• Hypergammaglobulinemia esp IgG (due to circulating autoantibodies), with normal IgM and IgA
• type 1 AIH autoantibodies: ANA, anti-smooth muscle (ASMA in 65% of patients), anti-actin antibodies (AAA), antimitochondrial antibody (AMA, rare unless there’s PBC overlap), atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA),
• type 2 AIH autoantibodies: Anti-liver kidney microsomal-1 antibody (ALKM-1), Anti-liver cytosol-1 antibody (ALC-1), Anti-liver kidney microsomal-3 antibody (ALKM-3)
• type 1 and 2 AIH ab’s: Anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP in 10-30% pts), Anti-DNA antibodies (single stranded DNA [ssDNA] and double-stranded DNA [dsDNA] in 25-35% pts)
• higher antibody titers (>1:160) provide greater support for the diagnosis compared with lower titers
• Autoantibody negative autoimmune hepatitis occurs in 20% patients.. They are considered to have autoantibody negative autoimmune hepatitis or cryptogenic chronic hepatitis.

Imaging:

• not routinely done. No characteristic features
• MRCP is done to exclude primary sclerosing cholangitis

Liver biopsy histopath:

• not required, but guides treatment.
• portal mononuclear cell infiltrate (lymphoplasmacytic, often with occasional eosinophils), invades the hepatocyte boundary (limiting plate) surrounding the portal triad and infiltrates into the surrounding lobule and beyond
• periportal lesion (sometimes referred to as piecemeal necrosis or interface hepatitis), spares the biliary tree but may involve more of the lobule
• Bile duct changes (eg, destructive and nondestructive cholangitis, ductal injury, and ductular reaction)
• plasma cell infiltrate, rosettes of hepatocytes, and multinucleated giant cells, may be seen
• Some degree of fibrosis

DDx:

• Primary biliary cholangitis
• Overlap syndromes: primary sclerosing cholangitis/autoimmune hepatitis
• Viral hepatitis: hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-Barr virus; cytomegalovirus
• Drug-induced liver injury
• Nonalcoholic steatohepatitis
• SLE-associated liver disease
• Iron overload: elevated serum ferritin +/- elevated transferrin saturation. Exclude genetic hemochromatosis

Treatment:

• glucocorticoid, with or without azathioprine or 6-mercaptopurine

Question 4

Primary biliary cholangitis / cirrhosis

Answer 4

Description:

- Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis

• characterised by immunologic attack on the intralobular bile ducts

Pathophys:

• T lymphocyte (CD4 and CD8) mediated auto-reactivity against small intralobular biliary duct epithelial cells –> leads to their gradual destruction ( “foamy” degeneration of hepatocytes) and eventual disappearance –> cholestasis –> noxious effects of bile acids
• auto-reactive B cells also play a role. They produce antimitochondrial antibodies that target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs (blood endothelial cells)
• Possible molecular mimicry with antimitochondrial antibodies (from IgM producing B cells), triggered post an infection. Hypothesised agents: retroviruses, Propionibacterium acnes, Chlamydia pneumoniae, E. coli, Novosphingobium aromaticivorans, Lactobacillus
• there is a genetic link. Increased chance with 1st degree relative.

Epidemiology:

• rare
• 90-95% are women, mostly 30-65yo
• Associated with: autoimmune thyroiditis, Sicca syndrome (dry eyes/mouth), scleroderma overlap (and may include CREST syndrome - Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia), Raynauds, RA, coeliacs, IBD

Clinical features:

• 50-60% asymptomatic at diagnosis (detected due to deranged LFTs)
• pruritis (precedes onset of jaundice) and fatigue (daytime somnolence) are most common. Mitochondrial effects laed to muscle acidosis and fatigue
• jaundice
• signs/syx of cirrhosis/ CLD inc portal HTN, jaundice, pruritus, signs of upper gastrointestinal bleeding, abdominal distension from ascites, confusion due to hepatic encephalopathy
• HCC
• metabolic bone disease (osteopenia and osteoporosis)
• intestinal malabsorption (fats, vitamins AEDK)

Examination:

• skin: hyperpigmentation (melanin deposition), jaundice (late manifestation), xanthomas, dry skin, fungal infections
• hepatosplenomegaly (marked) due to portal HTN
• spider nevi, temporal and proximal muscle wasting, ascites, oedema (from cirrhosis), Kayser-Fleischer rings from copper retention

Labs:

• LFT derangement (cholestatic - ALP >1.5 x upper limit)
• +ve antimitochondrial antibodies (AMA in virtually all pts - serological hallmark with titre > 1:40); +ve ANA (in 70% pts. “PBC-specific” patterns: multiple nuclear dots pattern (target antigen, Sp100) and the rim-like/membranous pattern (target antigens, gp210, nucleoporin p62, and the lamin B receptor)); may also have +ve anticentromere, anti-SSA/Ro, anti-dsDNA
• hyperlipidemia (can have cholesterol 1000mg/dL or >26mmol/L)
• eosinophilia. Anaemia (esp due to GI loss w portal HTN), thrombocytopenia, leukopenia
• others: high IgM, ceruloplasmin, bile acids (very high), hyaluronate

Liver biopsy:

• useful in staging and prognosis, and confirm diagnosis if clinical picture doesn’t fit (e.g. patient is male, has other comorbidities / systemic disease)
• Histopath: bile duct lesion of primary biliary cholangitis demonstrates bile ducts surrounded and invaded by primarily lymphocytes. There are several eosinophils. [refer to image of PBC histopath]
• staging:

●Stage 0: Normal liver

●Stage 1: Inflammation and/or abnormal connective tissue confined to the portal areas

●Stage 2: Inflammation and/or fibrosis confined to portal and periportal areas

●Stage 3: Bridging fibrosis

●Stage 4: Cirrhosis

Imaging:

• RUQ USS - r/o biliary obstruction

DDx:

• auto-immune hepatitis. Associated with high ALT, +ve anti smooth muscle antibodies, ANA, antiLKM 1 antibodies. AMA may be +ve. Elevated total IgG.
• other causes of cholestasis: gallstone disease or malignant duct obstruction (esp w acute onset jaundice), primary sclerosing cholangitis, drug-induced cholestasis (phenothiazines, synthetic androgenic steroids, bactrim, tolbutamide, and possibly diclofenac, oxacillin, and ampicillin), sarcoidosis, amyloidosis, viral hepatitis
• primary sclerosing cholangitis - no biliary obstruction present. AMA negative. Diagnosed with MRCP/ERCP

Treatment:

• 1st line: ursodeoxycholic acid (UDCA) 13-15mg/kg PO, bd. Assess response after 1year (normalisation of ALP). If so, continue to monitor 3-6monthly.

UDCA is a hydrophilic bile acid. Mechanism of action: (1) Increased hydrophilic index of the circulating bile acid pool. (2) Stimulation of hepatocellular and ductular secretions. (3) Cytoprotection against hydrophobic bile acid- and cytokine-induced injury. (4) Immunomodulation and anti-inflammatory effects

• 2nd line: If no response after 1yr, add obeticholic acid (do not use in decompensated liver disease) OR fibrate (bezafibrate 400mg daily) and re-assess after 6months
• 3rd line: Budesonide (but do not use in cirrhosis)
• Other measures: vaccinate for Hep A, Hep B, pneumococcal, influenza; EtOH abstinence; monitor LFTs and platelets every 3-6mo; Monitor yearly vitamin A, vitamin D, INR; Screen TSH for hypothyroidism; 2-yearly BMD scan; Endoscopy 2-3yearly in cirrhotic patients; 6-monthly liver USS for HCC screening.

Prognosis:

• now, only a minority of patients develops cirrhosis due to treatment with ursodeoxycholic acid (hence, name changed to primary biliary cholangitis)
• poor prognostic indicators: symptoms at time of diagnosis (advanced disease), high ALP and bili, advanced disease (on histology), ANA+, smoker, associated disorders (thyroiditis, sicca, scleroderma), complications of cirrhosis/portal HTN and decompensated CLD (ascites, SBP, variceal bleeds)
• GLOBE score: estimates the duration of transplant-free survival. 5 variables: serum bilirubin, albumin, ALP, platelet count after one year of UDCA treatment, and age at start of therapy.
• UK-PBC score: estimates the risk of liver transplantation or liver-related death. Score uses ALP, aminotransferases, and bilirubin after 12 months of UDCA therapy, as well as baseline albumin and platelet count.

Liver transplant:

• decompensated cirrhosis with complications such as variceal bleeding and hepatocellular carcinoma, despite medical therapy

Question 5

Cirrhosis

Answer 5

Causes:

Progression of NAFLD, alcoholic-related, portal hypertension, hepatocellular cancer

Labs:

• low albumin
• prolonged PT/INR
• thrombocytopenia, neutropenia

Question 6

HCC

Answer 6

USS:

• Advanced HCC is almost always multifocal, making it difficult to distinguish from metastatic disease.
• Small HCCs (<5 cm=””><5cm) are often (75%) hyperechoic. As HCCs grow, they tend to develop hypoechoic peripheral rims. With further progression, lesions become more numerous and heterogeneous.
• Fatty metamorphosis may cause increased echogenicity and confusion with hemangioma. Likewise, echogenic nodules are fairly common in multifocal HCC.
• Hepatic or portal venous invasion should suggest the diagnosis of HCC, although other liver tumors may invade veins.
• Rarely, HCC invades the bile duct.

Question 7

Liver transplant

Answer 7

Criteria:

• Patients who develop cirrhosis and have complications (eg, ascites, variceal bleeding)
• MELD (model for end-stage liver disease) score ≥10

Question 8

Hepatitis C

Answer 8

Epi:

50 - 85 % of patients with chronic hepatitis C infection develop chronic hepatitis.

Clinical features:

• slowly progressive. Many patients with infection are symptomatic
• generalised symptoms: fatigue and sleep disturbances; nausea, diarrhea, abdominal pain, anorexia, myalgia, arthralgia, weakness, and weight loss. Neuropsychiatric symptoms (eg, depression and anxiety)
• Abdominal pain, itching, and dark urine
• Extrahepatic manifestations ass w chronic HCV:

●Hematologic diseases, such as essential mixed cryoglobulinemia and lymphoma

●Renal disease, particularly membranoproliferative glomerulonephritis

●Autoimmune disorders, such as thyroiditis and the presence of autoantibodies

●Dermatologic conditions, such as porphyria cutanea tarda (generally “photosensitivity,” which causes painful, blistering lesions to develop on sun-exposed areas of the skin inc hands and face) and lichen planus (purplish, itchy, flat bumps that develop over several weeks)

●Diabetes mellitus

Cirrhosis:

5 to 30 percent of chronically infected individuals develop cirrhosis over a 20- to 30-year period of time.

Question 9

LFT interpretation

Answer 9

Upper limit of normal for LFTs:

• AST 32 (F), 40 (M)
• ALT 25 (F), 33 (M)
• ALP 100 (females), 115 (males)
• GGT 36 (F), 61 (M)
• Bilirubin 17

Aetiology of hepatitis based on LFTs [refer to image LFT interpretation]:

• AFLD: Moderate elevations of the AST and ALT (typically less than 300 int. unit/L, rarely higher than 500 int. unit/L). AST <8x ULN, ALT <5x ULN.

AST:ALT ratio ≥2

elevated INR, GGT, bili, leukocytosis with predominant neutrophils

• NAFLD – AST/ALT <4x ULN
• Ischaemic hepatitis, AST + ALT >50x ULN
• Acute viral hepatitis/Toxin related hepatitis (if jaundice present) – AST and ALT typically >25x ULN
• Chronic hepatitis C (variable) – normal to <2x ULN. Almost never >10x ULN
• Chronic hepatitis B – mild/mod elevations. Usually with exacerbations, almost never >10x ULN
• Paracetamol toxicity: Acute paracetamol toxicity also has a far higher elevation in aminotransferases (often >3000 IU/L), associated with rising INR. Chronic paracetamol toxicity is assocaited with high aminotransferases (>3000 IU/L) combined with hypovolemia, jaundice, coagulopathy, hypoglycemia, and acute renal failure in over 50% of these patients.

Chronic toxicity has AST:ALT ratio >2. Acute toxicity has lower ratio.

Question 10

Hepatitis B

Answer 10

Exposure:

• sexual contact, IVDU, needle stick injury, breast milk

PEP:

• single dose hep B IVIG (within 72hrs of exposure, for vaccine non-responders or HbsAb <10IU/mL)
• 3 x doses hep B vaccine over 6months (when hep b s Ab <10mIU/mL; administer vaccines within 7days of exposures)
• serology to prove seroconversion / immunity at 6wks, 3mo, 6mo.
• Should seek treatment within 24hrs. The longer a person waits, the less effective treatment is.
• consider testing for hep C and HIV
• source: https://www.health.qld.gov.au/__data/assets/pdf_file/0016/151162/qh-gdl-321-8.pdf*

Question 11

Urea Cycle Disorders

Answer 11

Description:

• Urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body
• UCDs occur when there is Deficiency of an enzyme in the pathway
• UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening metabolic decompensations in infancy. Survivors of the metabolic decompensation frequently have severe neurologic injury.

Pathway [refer image]:

• The urea cycle converts nitrogen from peripheral (muscle catabolism) and enteral sources (protein ingestion), into urea, which is water soluble and can be excreted from the body.
• six enzymes are involved in the cycle
• excess carbamyl phosphate (CP) flows into pyrimidine synthesis and, hence, to orotic acid, which is excreted in the urine.
• nitric oxide (NO) is generated when arginine is converted into citrulline by nitric oxide synthase (NOS).
• ornithine and citrulline transporter (ORNT1; SLC25A15), and cationic amino-acid transporter is found on intestinal- and kidney-epithelial cells (SLC7A7).
• citrin a mitochondrial aspartate and glutamate transporter (SLC25A13), is also involved

Types of deficiencies:

●Carbamyl phosphate synthetase I (CPSI) deficiency (MIM #237300)

●Ornithine transcarbamylase (OTC) deficiency (MIM #311250)

●Argininosuccinate synthetase (ASS) deficiency [2] (also known as classic citrullinemia or type I citrullinemia [CTLN1] MIM #215700)

●Argininosuccinate lyase (ASL) deficiency [3] (also known as argininosuccinic aciduria, MIM #207900)

●N-acetyl glutamate synthetase (NAGS) deficiency (MIM#237310)

●Arginase deficiency [4] (MIM #207800)

Inheritence:

• autosomal recessive, with the exception of ornithine transcarbamylase (OTC) deficiency (which is X linked).

Clinical features / presentation:

• Severe defects typically present in term newborns who appear well for the first 24 to 48 hours after birth. The infant becomes symptomatic after feeding has started because human milk or infant formula provides a protein load.
• Initial signs include somnolence, inability to maintain normal body temperature, and poor feeding, usually followed by vomiting, lethargy, and coma
• common early sign of hyperammonemia is central hyperventilation leading to respiratory alkalosis.
• the absence of risk factors for sepsis and a nondiagnostic sepsis evaluation should prompt consideration of a metabolic disorder

Question 12

Wilsons disease

Answer 12

Description:

• a genetic abnormality inherited in an autosomal recessive manner that leads to impairment of cellular copper transport
• Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver (overtime becomes cirrhotic), brain, and cornea

Epi:

• prevalence of approximately one case in 30,000 live births
• Liver disease: 18 to 84 percent of patients. Children moreso present w liver manifestations initially
• Neurologic symptoms: 18 to 73 percent of patients. Adolescents moreso present with neuro syx initially
• Psychiatric symptoms: 10 to 100 percent of patients

Presentation:

• majority of patients with Wilson disease are diagnosed between the ages of 5 and 35 years (mean age of dx 13 years)

Hepatic disease (steatosis, acute/chronic hepaitis, acute/chronic liver failure, cirrhosis) and manifestations:

●Kayser-Fleischer rings, visible in 50 percent of patients with hepatic disease (seen with all forms of liver involvement)

●Asymptomatic (steatosis, chronic hepatitis, compensated cirrhosis)

●Abdominal pain (acute hepatitis, acute liver failure)

●Jaundice (acute hepatitis, acute liver failure, cirrhosis)

●Hepatomegaly (acute and chronic hepatitis, acute liver failure)

●Splenomegaly (cirrhosis)

●Ascites (cirrhosis)

●Upper gastrointestinal bleeding (cirrhosis with varices or portal hypertensive gastropathy)

●Peripheral stigmata of chronic liver disease (cirrhosis)

●Mental status changes due to hepatic encephalopathy (acute liver failure, cirrhosis)

Neurologic disease manifestations:

●Dysarthria – 85 to 97 percent of patients with neurologic Wilson disease

●Gait abnormalities/ataxia – 30 to 75 percent. Dysmetria (pass-pointing), dysrhythmia (abn finger tapping)

●Dystonia – 11 to 69 percent

●Tremor – 22 to 55 percent. Rest or action, task-dependent. May resemble essential tremor (arms, sometimes head) but can be asymmetricle; intention tremor; postural tremor (wing-beating); unilateral rest tremor

●Parkinsonism – 19 to 62 percent. bradykinesia, cogwheel rigidity, and postural instability.

●Drooling – 48 to 86 percent

● Chorea - seen moreso in younger patients

Psychiatric/behavioural manifestations:

• 20-30% patients

●Depression

●Declining school performance

●Personality changes (which may be subtle)

●Irritability

●Impulsiveness (frontal syndrome)

●Labile mood

●Sexual exhibitionism

●Inappropriate behavior

●Dysthymia

●Bipolar affective disorder

●Psychosis

Other manifesations:

• Hemolysis
• Kayser-Fleischer rings
• Fanconi syndrome (renal tubular acidosis)
• arthropathy

Diagnostic criteria - refer to image

• includes ceruloplasmin level, slit lamp exam, 24hour urinary copper

Labs:

• low serum ceruloplasmin <200mg/L or 20mg/dL (sign of liver involvement. Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism)
• raised aminotransferases (ALT and AST typically <2000; AST:ALT often >2)
• elevated 24hour urinary copper >40mcg (0.64 micromol) with other criteria present
• elevated serum copper
• coagulopathy, thrombocytopenia, anaemia
• CSF: elevated copper 3-4 x above normal

Imaging:

• hepatic steatosis or cirrhosis. Splenomegaly
• Brain: basal ganglia abnormalities