Alcoholic/Nonalcoholic/Inherited Liver Disease Flashcards

Question

Nonalcoholic Fatty Liver Disease

Answer 1

- acquired liver disease in children & adults - inc. w/epidemic of obesity in US - macrovesicular hepatic steatosis - ethanol <20gm per day

Answer 2

1. Steatosis 2. Non-Alcoholic Steatohepatitis (NASH) - fatty liver, fibrosis and cirrhosis described in obease patients, (NASH was originally separate)

Answer 3

- excess body fat in relation to lean body mass - BMI > 30 - BMI = weight/height^2

Answer 4

-NAFLD: 20-30% of adults, 10% kids -by 2025, over 25 million Americans are predicted to have NAFLD related to liver disease -next epidemic for liver disease Fatty Liver: 10-15% of normal individuals -70-80% of obese NASH: 3% of normal, 15-20% of morbidly obese (BMI>35)

Answer 5

- obesity - Type 2 Diabetes - Hyperlipidemia - Metabolic Syndrome

Answer 6

- Race/Ethnicity: mexican americans have the highest africans lowest - Gender: initially more women, now 50/50 - Familial component: diet, genetics

Answer 7

-10% of kids -leading cause of pediatric liver disease 130 with liver biopsy: median age 12, 87% had fibrosis, 20% had bridging fibrosis -in 100 with NASH: 8% advanced fibrosis, 3% cirrhosis

Answer 8

1. Nutritional Abnormalities: total parenteral nutrition, starvation, refeeding 2. Metabolic Diseases: abetalipoproteinemia, hypobetalipoproteinemia 3. Occupational Chemical Exposure 4. Drugs: tamoxifen, corticosteroids, amiodarone, methotrexate, anti-retroviral therapy 5. Surgery: rapid, excessive wt loss (jejunoileal bypass)

Answer 9

-fatty liver: limited progression -NASH: 30-40% with advanced fibrosis 10-15% with cirrhosis -NASH induced cirrhosis is an increasing cause of Hepatocellular Carcinoma

Answer 10

- normally triglycerides incorporated into chylomicrons (travel via lymphatics to peripheral fat), hydrolyzed to free fatty acids (stored in liver, oxidized by mirochondria (triglyceride/cholesterol formation)) - Steatosis: a result of disturbed balance (more lipogenesis/increased FFA)

Answer 11

- insulin promotes uptake of glucose (stored as glycogen) - inhibits lipolysis - increased levels of insulin lead to increased lipogenesis, increased FFA - increased mitochondrial fatty acid oxidation (free radical formation & damage)

Answer 12

-increase in synthesis of free fatty acids (FFA) -decrease in oxidation of FFA Insulin Resistance -increase in adipose tissue lipolysis, increased FFA

Answer 13

- fatty liver | - increased oxidative stress, increased free radicals, direct liver injury

Answer 14

1. hepatic fat accumulation | 2. oxidative stress via lipid peroxidation and free radicals

Answer 15

- Hep C + NASH - Hemochromatosis + NASH - Alpha 1 antitrypsin deficiency + NASH - alcohol + NASH

Answer 16

- most have no symptoms or signs of chronic liver disease | - nonspecific symptoms: fatigue

Answer 17

- weight reduction (10%) - if diabetic: control - if hyperlipidemic: treat (inc. cardiac risk) - no magic meds

Answer 18

- Hepcidin - Ferroportin (baso-lateral surface of enterocytes/macrophages; regulates Fe export - HFE gene protein (exact mechanism of action unknown) - HJV, BMP 6

Answer 19

- Principal iron-regulatory hormone - Regulation of Hepcidin release is the central mechanism in the pathogenesis of HH - Expressed predominantly in hepatocytes - Binds to ferroportin on basolateral surface of enterocytes and macrophages - Ferroportin internalized, inhibition of Fe release - Hepcidin expression is induced by excess iron and inflammation; expression decreased in fe deficiency, ineffective erythropoeisis - Mutations in HFE decrease Hepcidin expression leading to increased intestinal Fe absorption via up-regulation of ferroportin

Answer 20

Most common genetic disorder affecting Caucasians 1:200-250 in individuals of Celtic/Nordic origins Several types, most common (Type 1) is related to HFE gene mutations Inappropriately increased uptake of dietary iron Serum Iron is offloaded into tissues with High Transferrin Receptors Liver /Heart/Pancreas/Thyroid Increased oxidative stress generates Free radicals

Answer 21

85-90% due to mutations in HFE gene HFE gene defect described in 1996 C282Y/C282Y (80-85% of HH): G to A mis-sense mutation (tyrosine for cysteine) Other gene mutations: H63D, S65C homozygotes not associated with iron overload C282Y/H63D or C282Y/S65C may be associated with iron overload

Answer 22

Phenotypic expression (70%), End organ damage in only 10% Adult onset > 40 yrs men > 50 yrs women General: fatigue, arthritis (most common) Liver: Cirrhosis, hepatocellular carcinoma Heart: Restrictive Cardiomyopathy Pancreas: diabetes (formerly called bronze diabetes) Arthritis (second/third metcarpophalangeal joints)

Answer 23

Excess iron due to lack of Hepcidin (mutation at HAMP & HJV genes) Age of onset 10-15 yrs More cardiac involvement

Answer 24

Type III – Transferrin Receptor mutation ( similar to type 1) Type IVa and Type IVb caused by Ferroportin mutation Only few cases described worldwide

Answer 25

Confirms Excess tissue Iron Hepatic iron Index ( HIC/age) > 1.9 Assess the degree of Liver injury in patients with abnormal LFTs and Ferritin > 1000 - Diagnose Hemochromatosis in the absence of HFE mutation (type II, III)

Answer 26

Ineffective erythropoeisis (Thalassemia, Sideroblastic anemia) Parenteral iron overload (long term HD, blood transfusions) Chronic liver disease Aceruloplasminemia Congenital atransferrinemia

Answer 27

Recommended for all first degree relatives Check Ferritin/TS and HFE mutation analysis For children of a pro-band, sufficient to check other parent, if normal then children are heterozygotes and do not need further testing Homozygotes/compound heterozygotes with elevated Ferritin should initiate therapeutic phlebotomies; If Ferritin levels are normal then monitor Fe studies annually

Answer 28

Focus is on removing excess iron ( irrespective of gene mutation) Phlebotomy - may need several weeks ``` Iron Chelating Agents: ( Binds Iron and removed through urine) -Desferoxamine Intravenous -Deferasirox (Exjade) Oral - useful when patient has low hemoglobin (Thalassemia, sickle cell) ``` Avoid vitamin C (increases Fe absorption) Decrease alcohol intake Decrease Dietary iron intake (no longer recommended) -Avoid Undercooked seafood risk of Vibrio vulnificus -Patient are high risk of infections with siderophilic “iron loving” Bacteria Listeria, Yersinia

Answer 29

``` Autosomal recessive disorder 1st described in 1912 by Kinnear Wilson Excessive Cu deposition Target Organs (Major) Liver: Chronic Hepatitis, Cirrhosis Brain: Basal Ganglia, Psychiatric Kidneys: Proximal tubular disease ATPase Deficiency ```

Answer 30

Liver disease (presents earlier in life); wide spectrum (Abnormal LFTs, Cirrhosis, ALF) Neurological disease (Parkinson like symptoms; tremor, dysarthria, dystonia, lack of motor coordination, spasticity, dysphagia) Psychiatric disease Other organ involvement (Cardiomyopathy, Pancreatitis, Osteoporosis, Arthritis, Nephrolithiasis) Kayser-Fleisher Ring (deposti in cornea)

Answer 31

Acute presentation of a Chronic Disease Clinical Liver Failure: Encephalopathy, Coagulopathy Hemolytic Anemia ( Coomb's negative) Low serum Alkaline Phosphatase; ALP/Bil < 2 AST/ALT < 2000 Treatment Only Treatment is Liver Transplantation

Answer 32

Any patient < 40 yrs with elevated AST/ALT Neuropsychiatric disease with liver disease Any young patient with liver failure Presentation at age < 5 yr or > 40 yr is unusual but possible

Answer 33

Serum Ceruloplasmin - ( Normal 20-50 mg/dl) - 95% of Wilson disease pts have low ceruloplasmin - Can be low in patients with decompensated liver disease of any etiology - levels < 5 mg/dl are highly suggestive of underlying Wilson’s -Serum total Cu - 3.15x Ceruloplasmin = non Ceruloplasmin (free) Cu -Total Copper is usually low (due to low Ceruloplasmin) -Free Copper >25 µgm/dl is typical of Wilson’s -Mild increase in other cholestatic liver diseases Liver Copper Concentration > 250 µgm/gram False Negative Advanced liver disease with severe fibrosis

Answer 34

Difficulties 1. There are multiple mutations causing defective protein ( unlike Hemochromatosis where a single mutation causes the disease) 2. Polymorphism of normal gene ( non disease causing mutations) 3. So genetic testing is feasible only if you have an index case ( family member)

Answer 35

``` Medical 1. Chelating agents Penicillamine Trientene Tetrathiomolybdate 2. Zinc ``` Liver Transplantation

Answer 36

Penicillamine (chelates copper) 10% may not tolerate due to side effects Pyridoxine SE: Lupus, hepatotoxicity, neuropathy, GI side effects Trientene (chelates copper) 250 qid, SE: sideroblastic anemia Zinc (decreases the absorption of Copper) SE: GI symptoms Trientene + Zinc is probably the Rx of Choice

Answer 37

A protein (314 Amino Acids) produced by the Liver Neutralizes neutrophil elastase activity Proper secretion from liver is essential for normal serum levels

Answer 38

Phenotype: the two types of molecules from each parent Example: Phenotype MZ One molecule is M (one parent) and Second molecule is Z (from other parent) Phenotypes: MM,MZ, MS, ZZ, SS, ZZ Liver disease is seen only with ZZ type and some SZ type

Answer 39

- Cirrhosis of undetermined etiology - Emphysema with liver disease - Emphysema (especially in non smokers) Diagnosis -Phenotype disease phenotype is ZZ -Liver Biopsy showing Alpha 1 AT granules

Answer 40

STOP SMOKING 1. Replacement α AT (IV infusion) Useful for emphysema Not useful for liver disease 2. Rx of patient with cirrhosis Liver transplantation

Answer 41

1. Hemochromatosis Disease can theoretically recur (clinically not seen) No Impact on extrahepatic sites (cardiac) 2. Wilson’s Disease OLT cures the disease, No recurrence Neurological disease may improve 3. Alpha 1 Antitrypsin Deficiency OLT cures the hepatic disease Emphysema is irreversible ( further pulmonary damage may be prevented)