Ch. 14 Alcoholic Liver, Congenital, Porphyrias Flashcards
Clearance of this toxin from the body occurs in a linear fashion. Its consumption causes a spectrum of liver disease. Name the toxin, the three main pillars of the spectrum, which are reversible, and whether this will cause a greater elevation of AST or ALT
What four things does this toxin do to hepatocytes directly?
Alcoholic Liver Disease
Fatty Liver->Acute alcoholic hepatitis->Cirrhosis
This process is reversible with abstinence at fatty liver disease.
AST is greater
Alcohol increases fatty acid synthesis, decreases mitochondrial oxidation of fatty acids, increases production of triglycerides, impairs release of lipoproteins–>all these produce the fatty liver with hepatocytes distended by fat
Pharm crossover: chronic alcohol use also augments metabolism of hepatic toxins, exaggerating the danger of agents usch as acetaminophen
Characterized by hepatocyte necrosis, Mallory bodies, neutrophilic inflammatory infiltrate, and perivenular fibrosis with an AST greater than ALT
What are Mallory Bodies aggregates of?
Clinical Features?
Rx?
Alcoholic Hepatitis
Aggregates of intermediate filaments
Malaise, anorexia, fever, RUQ pain and jaundice. Leukocytosis common.
Rx: Corticosteroids if severe
Characterized by steatosis, lobular and portal inflammation, hepatocyte necrosis, Mallory bodies and fibrosis with a history ofobesity, type 2 diabetes mellitus, hyperlipidemia, and religious avoidance of alcohol
Non-alcoholic fatty liver disease
In real life, its a diagnosis of exclusion
ALT will be greater/similar to AST
Middle aged women presents with fatigue and pruritus. The patient has elevated serum alkaline phosphatase and is positive for circulating antimitochondrial antibodies.
What type of hypersensitivity is this?
What serum level increases strikingly and can lead to complications?
What is commonly a late complication?
Primary biliary cirrhosis (cholestatic liver disease with destruction of INTRAHEPATIC bile ducts)
Type IV (CD8)
High serum cholesterol lead to cholesterol-laden macrophages in subcutaneous tissues where they form localized lesions termed xanthomas.
Steatorrhea from bile excretion impairment–>Malabsorption of Vit D and Calcium cause osteomalacia and osteoporosis
Late complication: Cirrhosis
Two thirds of patients with this disease have ULCERATIVE COLITIS. Associated with HLA B8, hypergammaglobulinemia, and circulating P-ANCA
High risk of progressing to?
Imaging Sign!?
Primary Sclerosing Cholangitis (INTRA/EXTRAHEPATIC inflammation->fibrosis->obliteration->secondary biliary cirrhosis)
Can progress to Cholangiocarcinoma
Imaging: Dilation resulting in biliary beading
Clinical hallmarks include cirrhosis, diabetes, skin pigmentation, and cardiac failure most commonly due to an abnormal HFE protein due to a mutation in C282Y. Name the disease. Can you explain the molecular mechanism behind this (Bonus I hope)?
Common pancreas related complication?
Labs: (ferritin, TIBC, serum iron, percent iron saturation)
Diagnosis?
Damage mediated by?
Can lead to which neoplasm?
Rx?
Whats the most important regulator of plasma iron
Hereditary Hemochromatosis
Mutant HFE protein cannot promote iron uptake, leading to a perceived deficiency. Duodenal crypt cells sense an iron deficiency, upregulating DMT-1 and ferroportin which leads to excess absorption of dietary iron
Pancreas: Diabetes (Bronze diabetes due to skin pigment)
Lab: High ferritin, Low TIBC, High serum iron, High percent saturation
Diagnosis: Prussian blue stain for iron in hepatocytes (on gross exam lipofuscin (ago spots for the liver) look the same…NEED THE STAIN)
Damage: Fenton reaction generated free radicals
Can lead to hepatocellular carcinoma
Rx: Weekly phlebotomies (like polycythemia vera)
Regulator: hepcidin->controls iron levels by binding ferroportin
Massive iron overload can occur in patients with hemolytic anemias, such as sickle cell and thalassemia major. Why is that?
Because we commonly transfuse blood, and each bag of blood is like giving a bag of iron since we have no effective mechanism for eliminating high amounts of iron. As a result, Secondary Iron Overload occurs.
Deficient incorporation of this toxin into ceruloplasmin and biliary excretion. Name the toxin. Name the disease. Name the mutation.
Name the common sign we LOOK for and the membrane these are present in.
Labs?
Damage is mediated by?
Increased risk of?
Copper
Wilsons Disease
ATP7B
Kayser-Fleischer rings in the Descemet membrane
Labs: Increased urine copper, decreased serum ceruloplasmin
Hydroxyl free radicals lead to tissue damage (Cirrhosis and neurologic manifestations)
Risk: Cirrhosis leading to Hepatocellular carcinoma
Your attending seems very concerned that baby Gunner’s infant screening exam has shown the Pi genotype ZZ and Gunner’s jaundice may not be simple neonatal jaundice. The attending asks you what your diagnosis is! Before you can answer, baby Gunner sits up and shouts…
Thankfully baby Gunner hasn’t had time to memorize Rubins and Symptoms to Diagnose. What staining would we use on the liver to visualize this disease?
Complication and Rx?
“I have a1-Antitrypsin deficiency!”
Periodic acid-Schiff (PAS) w/diastase digestion–>we will see red cytoplasmic granules
Protein aggregation in the ER
Complication: Cirrhosis and Emphysema
High incidence hepatocellular carcinoma too
Rx: Transplant
Inborn errors of carbohydrate metabolism (LOW YIELD):
- Branching enzyme deficiency that is usually complicated by cirrhosis
- Glucose-6 phosphate deficiency, severe hepatomegaly
- Acid-glucosidase deficiency (α-1,4-glucosidase), mild hepatomegaly
- Deficient glycogen debrancing enzyme, severe hepatomegaly
- Galactose-1-phosphate uridyl transferase missing, fibrosis progreses to cirrhosis by 6 months
- Deficiency of fructose-1-phsophate aldolase, progressive fibrosis culminates in cirrhosis
- Deficiency of fumarylacetoacetate hydrolase with high incidence of hepatocellular carcinoma
- Andersen disease
- Von Gierke
- Pompe disease
- Cori disease
- Galactosemia (type 1)
- Hereditary fructose intolerance
- Tyrosinemia
What’s the most common cause of acute liver injury? (Don’t keep reading and cheat!)
- Drug induced injury that can occur with low frequency, irrespective of dose and without obvious predisposition
- What is the most common cause of acute liver failure in the United States and is frequently seen in suicidal gestures?
- What are two drugs that can pure cholestasis?
Drugs
1. Idiosyncratic reaction!
Metabolic or genetic predispositions may cause unusual sensitivity to a dose-related side effect (ex. metabolic idiosyncrasy or autoimmune hepatitis)
There is no specific diagnostic test to predict or to diagnose drug-induced hepatotoxicity
2. Acetaminophen-induced hepatotoxicity
3. Estrogens and many antibiotics (esp sulfamethoxazoles)
Side note: inflammatory infiltrate, no matter what its composition, is not specific for drug-associated hepatotoxicity
What is worse, macrovesicular or microvesicular steatosis?
Explain Reye sydrome and which pattern of injury this is.
Microvesicular fatty liver is associated with severe and sometimes fatal liver disease, fat vacuoles are manifestations of metabolic injury to mainly the mitochondria
Reye is microvesicular with hepatic failure and encephalopathy following a febrile illness in CHILDREN, commonly influenza, with the administration of aspirin
- Deficiency of porphobilinogen deaminase that leads to colicky abdominal pain and neuropsychiatric symptoms
- Acquired or inherited disorder with a deficiency of uroporphyrinogen decarboxylase leading to cutaneous photosensitivity and hepatic iron overload
- Acute intermittent porphyria
2. Porphyria cutanea tarda
