Liver and Spleen

Liver and Spleen

LIVER

Architecture of the liver

The hepatic lobule is the structural unit of the liver.

hexagonal arrangement of plates of hepatocytes radiating outward from a central vein in the center.

At the vertices of the lobule are regularly distributed portal triads, containing a bile duct and a terminal branch of the hepatic artery and portal vein.

Vasculature of the liver

• 75% of the blood entering the liver is venous blood from the portal vein
• The PV is the confluence of the splenic vein and the superior mesenteric vein, which drain the small intestine, pancreas, stomach, and spleen.
• The remaining 25% of the blood supply to the liver is arterial blood from the hepatic artery.
• Terminal branches of PV and HA empty together and mix as they enter sinusoids in the liver.
• Sinusoids are distensible vascular channels lined with highly fenestrated endothelial cells and bounded circumferentially by hepatocytes.

• As blood flows through the sinusoids, a considerable amount of plasma is filtered inthe space between endothelium and hepatocytes (the "space of Disse"), providing a major fraction of the body's lymph.
• Blood flows through the sinusoids and empties into the central vein of each lobule.
• Central veins coalesce into hepatic veins, which leave the liver and empty into the vena cava

Biliary anatomy

• A series of channels and ducts that conveys bile from the liver into the lumen of the small intestine.
• Hepatocytes are arranged in "plates" with their apical surfaces facing and surrounding the sinusoids. The basal faces of adjoining hepatocytes are welded together by junctional complexes to form canaliculi, the first channel in the biliary system.
• A bile canaliculus is not a duct, but rather, the dilated intercellular space between adjacent hepatocytes.
• Hepatocytes secrete bile into canaliculi
• These secretions flow parallel to the sinusoids, but in the opposite direction to blood
• Bile flows into bile ducts at the end of the canaliculus,, which is a true duct lined with epithelial cells. Note bile ducts begin in very close proximity to the terminal branches of the portal vein and hepatic artery,
• The grouping of bile duct, hepatic arteriole and portal venule is called a portal triad.

Lymph formation

• Approx half of the lymph formed in the body is formed in the liver.
• Fenestrations in sinusoidal endothelial cells allow fluid and proteins in blood to flow freely into the space between the endothelium and hepatocytes known as the space of Disse forming lymph.
• Lymph flows through the space of Disse to collect in small lymphatic capillaries associated with the portal triads and from there into the systemic lymphatic system.

Lymph flow in the liver

If pressure in the sinusoids increases above normal, there is a corresponding increase in the rate of lymph production.

In severe cases this leads to exudation of lymph from the normal channels, and it accumulates in the abdominal cavity as ascitic fluid.

The Liver in phagocytosis

• The liver forms an important part of the phagocytic system.
• Macrophages known as Kupffer cells are situated in the sinusoids.
• Kuppfer cells are actively phagocytic and represent the main cellular system for removal of particulate materials and microbes from the circulation.
• They are located downstream to the blood entering the liver from the gut throught the portal vein . This allows it to effectively police and destroy bacteria entering the liver through breaks in the intestinal epithelium

Physiology of the liver

Functions

• Metabolism, Heat production
• Storage
• Excretion
• Detoxification
• Endocrine
• Bile production

Metabolism

• Products of digestion are transported by the portal venous system to the liver
• In the liver there are metabolised into products easily used by the body as energy
• Fats-in food
  • triglyceride
  • Phospholipids
  • sterols (principally cholesterol)
• Fats provide 9kcal/g, compared with 4 kcal/g for carbohydrate and protein.

Fat metabolism

• Oxidizises triglycerides to produce energy.
• After digestion, most of the fats are carried in the blood as chylomicrons.
• The main pathways of lipid metabolism are lipolysis, betaoxidation, ketosis, and lipogenesis.
• The liver synthesizes and secretes VLDL which is used to facilitate the Beta oxidation of fatty acids if energy is needed from this source
• The liver synthesizes large quantities of cholesterol and phospholipids. Some of this is packaged with lipoproteins and made available to the rest of the body. The remainder is excreted in bile as cholesterol or after conversion to bile acids.

Protein metabolism

• Peptidesamino acids in the liver. These can be used for gluconeogenesis
• The liver synthesizes all non essential amino acids
• Removal of ammonia from the body by synthesis of urea. Ammonia is very toxic and if not rapidly and efficiently removed from the circulation, will result in central nervous system disease.
• Also synthesizes plasma proteins and enzymes
  • Albumin
  • Fibrinogen

Carbohydrate metabolism

• Processes include
• Glycogenesis Excess glucose entering the blood after a meal is rapidly taken up by the liver and sequestered as the large polymer, glycogen
• Glycolysis-releases energy from glucose or glycogen
• Gluconeogenesis-formation of glucose from noncarbohydrate sources, such as certain amino acids and the glycerol fraction of fats when carbohydrate intake is limited.

Storage

• Vitamins ADEK
• Minerals eg Copper iron, Ferritin
• Glucose in the form of gycogen

Excretion

Ammonia

• formed by the breakdown of proteins
• converted into urea

Bacteria

• Kupffer cells

Cholesterol and bile pigments

Hormones- Degraded by the cytochrome p450 system

• Steroid hormones(oestrogen)
• Protein hormones(insulin, ADH)
• Catecholamines

Drugs and toxins

• Degraded by the cytochrome p450 system

Bile Production

Bile consists of

Products for excretion

• Bile pigments(red blood cells)
• Cholesterol(fat metabolism)
• Fat soluble drugs and toxins

Products to aid digestion

• Bile salts to emulsify fats(cholic ,chenodeoxycholic acid)
• Lecithin to help make cholesterol soluble
• Inorganic salts-including bicarbonate to neutralise duodenal contents

Enterohepatic circulation of bile salts

Bile salts aid solubility in the jejunum

Bacteria convert the bile salts into secondary acids

These are then resorbed in the terminal ileum as primary bile salts

These return to the liver via the portal circulation

Deficiency occurs in the context of disease or resection of the terminal ileum. This results in steatorrhoea and deficiency in fat soluble vitamins

Liver function tests-What’s it all about?

Alanine transaminase (ALT)

• an enzyme present in hepatocytes
• cell damage leaks it into the blood
• raised in acute liver damage eg viral hepatitis or paracetamol overdose.

Aspartate transaminase (AST)

• enzyme associated with liver parenchymal cells.
• not specific to the liver also present in red blood cells, and cardiac and skeletal muscle
• The ratio of AST to ALT is sometimes useful in differentiating between causes of liver damage.

Alkaline phosphatase (ALP)

• enzyme in the cells lining the biliary ducts of the liver
• rise with large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver.
• also present in bone

Total bilirubin

• breakdown product of heme (a part of haemoglobin in red blood cells).
• The liver is responsible for clearing the blood of bilirubin.
• In injury increased levels cause jaundice

• Direct versus indirect
• An increase in direct bilirubin/conjugated bilirubin suggests the problem is not being able to excrete it eg bile duct obstruction by gallstones or cancer.

• No increase in direct bilirubin suggests the liver is unable to conjugate bilirubin eg haemolysis, viral hepatitis, or cirrhosis

Gamma glutamyl transpeptidase (GGT)

• specific to the liver
• more sensitive marker for cholestatic damage than ALP
• may be elevated with even minor liver dysfunction
• raised in alcohol toxicity (acute and chronic). In some laboratories,

Coagulation test (e.g. INR)

• The liver is responsible for the production of coagulation factors
• only increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired

Serum glucose (BG, Glu)

• Gluconeogenesis I the last function to be lost in the setting of fulminant liver failure.

Lactate dehydrogenase (LDH)

• enzyme found in many body tissues, including the liver. Elevated levels may indicate liver damage.

Bilirubin excretion

Erythrocyteshemoglobin heme  unconjugated bilirubin in the kidney. (Not soluble in water)  bound to albumin  liver  conjugated with glucuronic acid(water soluble)

At this stage it can go down a number of routes

• goes into the bile and thus into the small intestine.
• conjugated bilirubin metabolised by colonic bacteria to urobilinogen  stercobilinogen  stercobilin(brown color of faeces)
• Some of the urobilinogen is reabsorbed and excreted in the urine

JAUNDICE

a yellowish discoloration of the skin, the conjunctival membranes over the sclerae and other mucous membranes

Due to hyperbilirubinemia

the concentration of bilirubin in the plasma must exceed three times the usual value for the coloration to be noticable

The classification of Jaundice

Pre hepatic	Hepatic	Post hepatic
Due to an increased rate of haemolysis eg malaria sickle cell anemia spherocytosis glucose 6-phosphate dehydrogenase deficiency Laboratory findings Urine: no bilirubin present Serum: increased unconjugated/indirect bilirubin	Cell necrosis reduces the liver's ability to metabolise and excrete bilirubin eg acute hepatitis hepatotoxicity alcoholic liver disease Congenital disorders Congenital hyperbilirubinaemia Metabolic defects in 1)intrahepatic conjugation Crigler-Najjar(unconj) 2)hepatic uptake Gilberts-5%, males, auto dominant 3)excretion of bilirubin Dubin-Johnson (conjugated)-recessive Rotor Syndrome Laboratory findings Urine: Conjugated bilirubin present	Leads to obstructive jaundice as there is blockage of bile flow eg. gallstones in the common bile duct pancreatic cancer in the head of the pancreas . Symptoms include presence of pale stools dark urine pruritus Laboratory tests liver function tests

Portal hypertension

A portal pressure gradient of >5mmHG(difference in pressure between the portal and hepatic veins)

Prehepatic causes

• Portal vein thrombosis

Hepatic causes

• Cirrhosis
• Hepatic mets

Post hepatic

• Budd Chiari(thrombosis of hepatic veins)

Budd-Chiari syndrome

Occlusion of the hepatic veins

Presentations

• abdominal pain
• ascites
• hepatomegaly

Eventually leads to encephalopathy

Genetic tendencies

• Protein C/Protein S deficiency
• the Factor V Leiden

Risk factors

• OCP, oestrogen containing
• Pregnancy
• Trauma

Treatment of BCS

• Surgical shunts to divert blood flow around the obstruction or the liver itself
• Transjugular intrahepatic portosystemic shunt (TIPS)
• - ower procedure-related mortality
• Angioplasty- stenosis or vena caval obstruction
• Liver transplant

Complications of Portal hypertension

Splenomegaly

• sequestration of platelets
• Leukopenia, thrombocytopaenia-hypertrophy of splenic substance

Ascites

•  Albuminintravascular oncotic pressure
• Lymphatic overflowlymph flow through thoracic duct exceeds capacity
• aldosteroneNa & H2O retention

Portosystemic shunting varices

• Gastric, oesophageal
• Periumbilical
• Retroperitoneal
• Rectal
• Diaphragmatic

Acute Liver injury

Causes

• Viral
• Alcohol
• Drugs
• Obstruction

Viral Hepatitis

Hepatitis A	Hepatitis B	Hepatitis C
Faeco-oral spread No carrier state Incubation period-15-40 days Serology- IgM class antibody to HAV	Spread- blood, needles venerally Carrier state exists Incubation period-50-180 days Serology HbsAg-Hx of infection HbeAg active infection Long term sequelae Chronic hepatitis Cirrhosis Implicated in pathogenesis of hepatocellular carcinoma	Spread- blood, needles venerally Carrier state exists Incubation period-40-55 days Serology- Anti-HCV antibody Increase in transaminases Sequelae chronic state cirrhosis

Alcoholic liver injury

Pathogenesis

• Cellular energy diverted to metabolism of alcohol-accumulation of fat in liver cells
• Alcohol metabolites bind to liver proteins-injured hepatocytes
• Alcohol stimulates collagen synthesis- fibrosis and cirrhosis
• Linking of portal tracts by fibroblasts- nodular regeneration of liver cells

Histology

• Steatosis-fatty change
• Mallory’s hyaline

Acute Biliary Obstruction

• Secondary to cholelithiasis
• If superimposed infection  cholangitis
• Bile accumulates in canaliculi and ducts
• extravasation of bile into liver tissue necrosis
• Repeated episodes of obstruction portal tract fibrosis& nodular regeneration
• 2 biliary cirrhosis

Chronic Liver Disease

Primary Haemochromotosis

• Excess Iron absorption from small intestine
• Defect at Chromosome 6 near HLA- A locus
• Iron accumulates in Kupffer cells, bile duct epithelium and portal tracts hepatic fibrosis cirrhosis
• Deposition of Fe in pancreatic islets Diabetes

Secondary Haemochromotosis

• Excess dietary iron
• Patenteral administration
• Excessive blood transfusion

Wilsons

• Inherited disorder of copper metabolism
• Copper accumulates in basal ganglia neurological disability
• Kayser Fleischer rings in cornea
• Labs- low ceruloplasmin
• Treatment-penecillamine

Alpha-Antitrypsin deficiency

Normally synthesized in the liver and excreted into blood

protects the lungs from the neutrophil elastase enzyme, which disrupts connective tissue

Carrier state exists

Homozygotes

• pulmonary emphysema
• hepatic cirrhosis

Treatment-

• IV infusions of A1AT protein
• liver or lung transplant

Autoimmune Liver Disease

• Autoimmune Hepatitis
• Primary biliary cirrhosis
• Sclerosing cholangitis

Autoimmune Hepatitis

• Females
• Histology-hepatitis
• Serology- autoantibodies found eg antinuclear antibody (ANA), smooth muscle antibody(SMA)
• Increased IgG level and transaminases
• Diagnosis always requires liver biopsy

Primary biliary cirrhosis

Females

Destruction of small intrahepatic ducts leading to cirrhosis

Copper accumulates in the liver

Serology

• ALP+ IgM
• Anti-mitochondrial antibodies

Features-Jaundice,Pruritus,Xanthelasma

Treatment-Liver transplant

Sclerosing Cholangitis

Chronic inflammatory process

Affects intra and extrahepatic ducts

Ducts are surrounded by inflammatory infiltrateimpedes the flow of bile to the gut, which can ultimately lead to liver cirrhosis and failure

underlying cause of the inflammation is believed to be autoimmunity.

Eventually leads to fibrosisobliteration of ductssecondary biliary cirrhosis

Associated with Ulcerative Colitis

Sclerosing Cholangitis

Labs

• pANCA
• ANA
• Anti-smooth ms antibodies
• Elevated bilirubin

Treatment

• Liver transplant

Associated with cholangiocarcinoma

TUMOURS

• Hepatocellular/ Hepatoma
• Cholangiocarcinoma
• Haemangioma
• Focal nodular hyperplasia
• Angiosarcoma
• Hepatoblastoma

HEPATOCELLULAR CARCINOMA

Highest incidence is seen in East Africa and South-east Asia

Male : female ratio = 4:1

In Europe peak age at presentation is 80 years

In Africa and Asia peak presentation is 40 years

Presentation

• Right hypochondrial pain/mass
• As with all malignancy- weight loss, loss of appetite
• Jaundice is a late sign

Aetiology

multifactorial

HBV infection (not independent risk factor)

HCV infection

cirrhotic liver

Mycotoxins - e.g. aflatoxin produced by Aspergillus flavus

Alcohol

Anabolic steroids

Primary liver diseases - e.g. primary biliary cirrhosis, haemochromatosis

Investigations

FBC

• Anaemia: Low hemoglobin may be related to bleeding from varices or other sources.
• Thrombocytopenia: A platelet count below 100,000/mL is highly suggestive of significant portal hypertension/splenomegaly.

U&Es

• Hyponatremia is commonly found in patients with cirrhosis and ascites and may be a marker of advanced liver disease.
• ↑creatinine intrinsic renal disease or hepatorenal syndrome.

Coag screen-

• ↑ INR -impairment of hepatic function that may preclude resection.

LFTs

• (AST/ALT) -active hepatitis due to viral infection, current alcohol use, or other causes.
• Increased bilirubin level -advanced liver disease.
• Glucose
• Hypoglycemia may represent end-stage liver disease (no glycogen stores).

Alpha-fetoprotein

• Foetal serum protein produced by the yolk sac and liver
• ↑serum levels seen in 70-90% of patients with HCC
• May be mild elevation ↑ in serum levels in the context of hepatitis and cirrhosis
• Serum levels correlate with tumour size
• Rate of increase in serum levels correlate with growth of tumour
• Tumour resection results in a fall in serum concentrations
• Serial assessment useful in measuring response to treatment

Finding the underlying cause

Hepatitic screen

• HBsAg/anti-HBc, anti-HCV - Viral hepatitis (current/past)

Iron studies

• Increased iron saturation (>50%) - Underlying hemochromatosis

alpha-1-antitrypsin levels

• Low in Alpha-1-antitrypsine deficiency

Tumour markers

• alpha fetoprotein - Levels greater than 400 ng/mL diagnostic

Staging

Prognosis is dependant on tumor characteristics

• Size
• Location
• Degree of underlying liver disease.

the tumor size is predictive of outcome, as it predicts the likelihood of major venous

The traditional pathological TNM (tumor, node, metastasis) staging system is used

Imaging

Ultrasound

• appears as a round or oval mass with sharp, smooth boundaries
• range of echogenicity, from hypoechoic to hyperechoic

Doppler analysis useful as HCC has a significant arterial blood supply in comparison to regenerative nodules

CT

• a hypervascular pattern with arterial enhancement
• tumor capsule
• variable attenuation within the tumor
• Smaller lesions may be missed
• 67% sensitivity

MRI

• sensitivity 81%

Hepatic decompensation

• Abnormal clearance of proteins absorbed from the intestine, leading to a build up of ammonia and hepatic encephalopathy (a build up of toxic substances such as ammonia that leads to nervous system changes and eventual brain damage).
• Elevated bilirubin levels, leading to jaundice.
• ascites
• Portal hypertension leading to varices

Treatment options

• Chemoembolization
• Ablation
• Chemotherapy
• Surgical resection
• Liver transplant

Radio-frequency ablation

Can extend life and potentially downstage the tumor to permit transplantation or resection.

A needle with an exposed electrode is inserted into the tumour under u/s guidance

Radiofrequency energy is emitted and is converted to heat in the electrode which causes tumour necrosis

Chemoembolization

Transcatheter arterial chemoembolization

Used mostly for palliative purposes

Performed by interventional radiologist

• cannulate the feeding artery to the tumor
• deliver high local doses of chemotherapy,eg mitomycin C.
• To prevent systemic toxicity, the feeding artery is occluded with coils to prevent flow.
• Note most hepatocellular carcinomas derive 80-85% of their blood flow from the hepatic artery, Normal parenchyma derives most of it’s blood supply from the portal vein so is largely unaffected by this procedure

Contraindicated in patients with advanced cirrhosis as it causes ischemic injury which can lead to a rapid decline in liver function with worsening encephalopathy, increased ascites, and, potentially, death.

Chemotherapy

• Hepatocellular carcinoma is minimally responsive to systemic chemotherapy.
• Doxorubicin-based regimens appear to have the greatest efficacy with response rates of 20-30%
• No apparent benefit with the use of adjuvant chemotherapy following resection

THE SPLEEN

Anatomy

Lies in LUQ

Along ribs 9, 10 and 11

Long axis lies along 10th rib

Concave inner surface related to:

• Tail of pancreas
• Stomach

Function

Haemopoiesis- In fetal life

Filtration of Blood Cells- Abnormal and old cells removed

Immunology-Cell mediated and humoral

Indications for Splenectomy

Trauma Indications:

• > 1L intraperitoneal blood
• > 2u RCC for transfusion
• Progressively decreasing Hb
• Haemodynamic Instability

Minor injury managed conservatively

Haemolytic anaemias

• Hereditary Spherocytosis-AD disorder: RCs are spherical
• Acquired Haemolytic Anaemias-due to : chemicals, drugs, infection, or it can be an immune phenomenon

Purpuras

• Idiopathic Thrombocytopaenic Purpura -autoantibodies cause platelet removal -causing bleeding with petechiae
• Secondary Thrombocytopaenia

Hypersplenism

• Normal function of spleen accelerates
• Gives rise to:-Splenomegaly: 90% of platelets and 45% of RCC, anaemia, leukopaenia, thrombocytopaenia
• Can occur in:-RA, malaria, myelo + lymphoproliferative disorders

Splenic Vein Occlusion

Caused by:

-pancreatitis

-portal HTN

-Pancreatic Ca

Myelofibrosis

Lymphomas

Miscellaneous:

• Splenic Cysts
• Haemangiomas
• Iatrogenic injury
• Malignant resections: gastric Ca, distal pancreas Ca

Preparation

• Bloods
• FBC + Coagulation
• Correct any abnormality
• RCC, FFP, platelets
• Preparation
• CT-To assess size of spleen pre-op
• Scintiscanning with 51 Cr labelled Rcs- To assess for accessory spleens ie to prevent relapse
• Prophylactic Abx
• NG Tube
• Can be Lap or Open

Vaccines- Pneumococcal, meningococcal and Haemophilus Influenza vaccines

-preferably given 3/52 pre-op

Complications

GENERAL

• Bleeding
• Wound Infxn
• GA
• VTE

Specific

• Pancreatitis: monitor amylase post op
• Pancreatic fistula
• Gastric fistula
• Acute gastric dilatation
• LLL collapse and atelectasis
• Subphrenic abscess: Morrisons pouch

Post Op Bloods

Platelets ↑- Can predispose to DVT/PE

WCC ↑

• Overwhelming Post Splenectomy Sepsis
• Rare: more common in kids
• Encapsulated bacteria: cannot be opsonized
• ? Lifelong penicillin V