Alcoholic/Nonalcoholic/Inherited Liver Disease Flashcards
Alcoholic Liver Disease: Epidemiology
- up to 41% of liver disease in Native Americans
- as high as 65% of all deaths from chronic liver disease in Native Americans
- 24% of chronic liver disease (40% deaths from cirrhosis)
- hospitalizations costs b/w $600 million and $1.8 billion/year
Ethanol Use in US
63% >18 drink
top 20% drink 80% of ethanol
top 2.5% drink 27% of ethanol
alcohol dependence/abuse 7.4% (11% men, 4% women)
Alcoholic Liver Disease
- steatosis
- alcoholic hepatitis
- alcoholic cirrhosis (hepatocellular carcinoma, cholangiocarcinoma)
Alcohol in Alcoholic Liver Disease
Ethanol >40-80gm/day
>5 year
(12gm is 12oz beer, 4oz wine, 1oz liquor)
Risk of Cirrhosis
3 drinks/day in women
differences in volume of distribution
dec. gastric alcohol dehydrogenase activity, particularly in younger adults
-differences in first pass metabolism
Men >6 or >10 drinks per day
only 9% ALD 6.4% cirrhosis
only 11.8% 8% cirrhosis
Alcoholic Hepatitis
- 40-60 years old
- > 80 gm/d > 5 years
- often >5 years
- rapid onset of jaundice
- fever, muscle wasting, ascites
- hepatomegaly with tenderness
- AST, ALT rarely over 300
- AST > 2x ALT
- frequent leukocytosis
- elevated INR
- prevalence unknown
- approximately 20% of 1604 alcoholic patients undergo liver biopsy
Alcoholic Hepatitis: Pathogenesis
- many proposed mechanisms of ethanol induced injury
- few animal models
- no one theory accepted
Alcoholic Hepatitis: Genetics
- concordance rate for alcoholic cirrhosis 3x higher in monozygotic twins than dizygotic twins
- in East Asians, functional polymorphisms of ADH2*1 gene were associated with increased susceptability to ALD
- in caucasians, the only replicated association is the TNF-alpha 238 polymorphism and ALD
Risk of Alcoholic Cirrhosis
1% >30-60gm/d
5.7% >120gm/d
Alcoholic Cirrhosis: Mechanisms
- ethanol, acetylaldehyde cause intestinal injury and increased permeability resulting in endotoxemia
- endotoxemia results in an inflammatory response by Kupffer cels
Two Hit Theory: Alcoholic Cirrhosis
1st Hit: Fatty Liver
-oxidative stress, inc. NADH/NAD ration, obesity and DM (genetics/diet), fat sensitizes liver to 2nd hit
2nd Hit: inflammation & necrosis, oxidative stress/hypoxia/immunological reaction
Alcoholic Hepatitis Predictors of Survival
- Maddrey Score
- Glasgow Alcoholic Hepatitis Score
- Model for End-Stage Liver Disease (MELD)
Advanced Liver disease in Alcoholics
- Hep C
- Hemochromatosis
- Alpha one antitrypsin deficiency
Ethanol + Hepatitis C
42% HCV
22% HCV + Ethanol
8% Ethanol
Ethanol + Hemochromaosis
- 15% of patients with hemochromatosis had ethanol abuse (>80gm/d)
- ethanol abuse associated with advanced fibrosis with hemochromatisos
- inc. cirrhosis and shorter survival than those without ethanol abuse
Ethanol + HFE mutations
conflicting data
- patients with ALD + C282Y mutations had more advanced fibrosis and cirrhosis
- HFE Heterozygousity “likely play some role in inc. iron loading and liver injury”
Ethanol + HFE
-alcoholic cirrhotic patients with heterozygous C282Y mutations had increased hepatic iron scores and higher rates of HCC
Ethanol + A1AT deficiency
-2.7% with phenotype (Caucasian Americans)
Alpha one Antitrypsin Deficiency
MZ or ZZ
- chronic hepatitis (8% alcoholic)
- cirrhotic (41% alcoholic)
Ethanol + Obesity
-ethanol patterns, obesity and associated hyperglycemia are the most important environmental factors determining ALD risk
Treatment of Alcoholic Liver Disease
- abstinence
- optimize nutrition
- pentoxifylline (TNF alpha inhibitor)
- immunosuppression with corticosteroids in select patients
- LIVER TRANSPLANT
Spectrum of Alcoholic Liver Disease
- steatosis
- perivenular fibrosis (central vein)
- alcoholic hepatitis
- sub-sinusoidal fibrosis
- cirrhosis
- hepatocellular carcinoma
Macrovesicular
-lipid filled vesicle is larger than the nucleus
Nonalcoholic Fatty Liver Disease
- acquired liver disease in children & adults
- inc. w/epidemic of obesity in US
- macrovesicular hepatic steatosis
- ethanol <20gm per day
2 conditions of Nonalcoholic fatty liver disease
- Steatosis
- Non-Alcoholic Steatohepatitis (NASH)
- fatty liver, fibrosis and cirrhosis described in obease patients, (NASH was originally separate)
Obesity
- excess body fat in relation to lean body mass
- BMI > 30
- BMI = weight/height^2
Nonalcoholic Fatty Liver Disease: Prevalence
-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)
NAFLD associated with?
- obesity
- Type 2 Diabetes
- Hyperlipidemia
- Metabolic Syndrome
Nonalcoholic Fatty Liver Disease: Epidemiology
- Race/Ethnicity: mexican americans have the highest africans lowest
- Gender: initially more women, now 50/50
- Familial component: diet, genetics
Pediatric NAFLD
-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
Other causes of NAFLD
- Nutritional Abnormalities: total parenteral nutrition, starvation, refeeding
- Metabolic Diseases: abetalipoproteinemia, hypobetalipoproteinemia
- Occupational Chemical Exposure
- Drugs: tamoxifen, corticosteroids, amiodarone, methotrexate, anti-retroviral therapy
- Surgery: rapid, excessive wt loss (jejunoileal bypass)
Natural History of NAFLD
-fatty liver: limited progression
-NASH: 30-40% with advanced fibrosis
10-15% with cirrhosis
-NASH induced cirrhosis is an increasing cause of Hepatocellular Carcinoma
NAFLD: Pathogenesis
- 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)
NAFLD: Pathogenesis (insulin resistance)
- 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)
NAFLD: obesity
-increase in synthesis of free fatty acids (FFA)
-decrease in oxidation of FFA
Insulin Resistance
-increase in adipose tissue lipolysis, increased FFA
NAFLD: increased FFA leads to?
- fatty liver
- increased oxidative stress, increased free radicals, direct liver injury
NAFLD: 2 hit hypohesis
- hepatic fat accumulation
2. oxidative stress via lipid peroxidation and free radicals
Concomitant Liver Desease
- Hep C + NASH
- Hemochromatosis + NASH
- Alpha 1 antitrypsin deficiency + NASH
- alcohol + NASH
NAFLD Clinical Features
- most have no symptoms or signs of chronic liver disease
- nonspecific symptoms: fatigue
Treatment of NAFLD
- weight reduction (10%)
- if diabetic: control
- if hyperlipidemic: treat (inc. cardiac risk)
- no magic meds
Regulation of Fe absorption and release?
- Hepcidin
- Ferroportin (baso-lateral surface of enterocytes/macrophages; regulates Fe export
- HFE gene protein (exact mechanism of action unknown)
- HJV, BMP 6
Hepcidin
- 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
Genetic Hemochromatosis
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
HFE gene mutations
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
Clinical Features of Hemochromatosis (Type I)
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)
Type II Hemochromatosis (HJV)
Excess iron due to lack of Hepcidin (mutation at HAMP & HJV genes)
Age of onset 10-15 yrs
More cardiac involvement
Hemochromatosis Type III & IV
Type III – Transferrin Receptor mutation
( similar to type 1)
Type IVa and Type IVb caused by Ferroportin mutation
Only few cases described worldwide
Diagnosis of HemochromatosisRole of Liver Biopsy
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)
Iron Overload (Secondary-Non Genetic )
Ineffective erythropoeisis (Thalassemia, Sideroblastic anemia)
Parenteral iron overload (long term HD, blood transfusions)
Chronic liver disease
Aceruloplasminemia
Congenital atransferrinemia
Screening for HFE
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
Treatment Hemochromatosis
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
Wilson’s Disease
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
Clinical Features of Wilson’s Disease
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)
Fulminant Liver Failure
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
When to suspect Wilson’s Disease
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
Wilson Disease: Diagnosis
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
Genetic Testing for Wilson’s Disease
Difficulties
- There are multiple mutations causing defective protein ( unlike Hemochromatosis where a single mutation causes the disease)
- Polymorphism of normal gene ( non disease causing mutations)
- So genetic testing is feasible only if you have an index case ( family member)
Treatment: Wilson’s Disease
Medical 1. Chelating agents Penicillamine Trientene Tetrathiomolybdate 2. Zinc
Liver Transplantation
Wilson’s Disease: Drugs
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
Alpha 1 ANTI TRYPSIN
A protein (314 Amino Acids) produced by the Liver
Neutralizes neutrophil elastase activity
Proper secretion from liver is essential for normal serum levels
α 1AT (Terminology)
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
When to suspect Alpha 1 Anti-trypsin?
Diagnosis?
- 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
Treatment for Alpha 1 Anti-trypsin?
STOP SMOKING
- Replacement α AT (IV infusion)
Useful for emphysema
Not useful for liver disease - Rx of patient with cirrhosis
Liver transplantation
Impact of Liver Transplantation
- Hemochromatosis
Disease can theoretically recur (clinically not seen)
No Impact on extrahepatic sites (cardiac) - Wilson’s Disease
OLT cures the disease, No recurrence
Neurological disease may improve - Alpha 1 Antitrypsin Deficiency
OLT cures the hepatic disease
Emphysema is irreversible
( further pulmonary damage may be prevented)
