Diseases and conditions Flashcards
Pemphigus
Autoantibodies against desmoglein 1 - predominates above the stratum sinosum of the epidermis
Pemphigoid
Larger lesions than pemphigus, all the epidermis is detached from the basal lamina, autoantibodies against bullous pemphigoid antigen BPAG1/2, a member of the plakin family connecting the basal lamina to the intermediate filaments
Atrophy - physiological and pathological
Physiological - Of thymus with age, of ovaries post-menopause, immobilisation of broken limbs
Pathological - Denervation/devascularisation
Hypertrophy - physiological and pathological
Physiological - Of uterus in pregnancy, Training
Pathological - Cardiomyocyte hypertrophy
Hyperplasia - physiological and pathological
Physiological - Adrenal cortex during stress, breasts in puberty and pregnancy
Pathological - Prostate, adrenal cortex due to ACTH insufficiency(?)
Metaplasia - physiological and pathological
Basal cells form a different type of epithelium:
Physiological - To establish simple columnar epithelium inside cervix, stratified squamous epithelium outside cervix, OR Barret’s oesophagus (stratified squamous to glandular)
Pathological - Bronchal metaplasia from inhaled particles, pseudostratified columnar to stratified squamous
Epithelial-mesenchymal transition - physiological and pathological
Physiological - Neural tube formation, wound healing
Pathological - Cancer metastasis
H. Pylori infection
Gram-negative bacterial infection of gastric atrium, can lead to gastric cancer/lymphoma, accounts for 90% of gastriris patients, breath test for diagnosis, antibiotics can treat lymphoma
Coeliac disease
Immune hypersensitivity to gluten - Inflammation damages villi, causes swelling and flattening, absorption becomes inefficient
Diverticular disease
Lack of fibre causes outward bulges or ‘diverticula’ in intestinal wall (diverticulosis), which can become inflamed, e.g. if impacted with faeces (diverticulitis)
Diverticulosis/itis
Capillaries on the exterior intestinal wall, which supply blood to colon epithelia (through diffusion/BM) cross through the muscle wall through small pores to reside under the intestinal epithelium, large pressures in the colon (obstruction/constipation) can cause the epithelium to bulge out through these pores
IBD - Ulcerative colitis
Colon only, autoimmune continous lesion (inflammation) from anus proximally onwards, limited to mucosa - can cause absence of Goblet cells, crypt distortion and abscesses
Symptoms - abdominal pain and bloody diarrhoea
Treat with steroids or foecal transplant
IBD - Crohn’s disease
Anywhere in GI tract, typically SI and sometimes LI
Immune, not strictly autoimmune - can be triggered
Inflammation occurs in ‘skip lesions’ and across the whole intestinal wall (transmural)
Diarrhoea not usually bloody
Biopsy - Granulomas, submucosal fibrosis, neuromuscular submucosal hyperplasia
Treat - steroids, lifestyle changes, palliative surgery, antibiotics for infection
Breast cancer - Molecular classification and typing
75% of all invasive breast cancers are ductal NST (No Special Type)
Luminal A: ER+ PR+ HER2-
Luminal B: ER+ PR+ HER2- Ki67+
Non-luminal: HER2-enriched and basal-like
80% of basal-like are also TN.
Lung cancer - Genetic factors and testing
EGFR (FISH gold standard, can use IHC)
ALK1 (IHC) - RTK, can fuse with TFG (like in Philadelphia Chr.); or inversion inv (2) (p21p23) results in ALK-EML4 gene fusion (NSCLC)
BMP9 binds ALK-1 and Endoglin -> Smad1/5/8 -> ID1/3/… transcription (inhibitor of DNA binding, promotes homologous recombination for DNA repair)
PDL1 (IHC) - Programmed Death Ligand 1 - Binds PD-1 to induce apoptosis in immune cells such as T cells - Mutations contribute to immune evasion in cancer
ROS1 (IHC & FISH)
RTK - can fuse with EZR (Ezrin, regulator of actin cytoskeleton)
Targets PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, JAK/STAT
Colorectal cancer - Molecular patterns
CIN (Chromosomal INstability) - Loss of entire chromosomes or large parts of them -> APC underexpression/mutation (adenoma induction) -> KRAS upreg. (adenoma growth), TP53 downreg (adenoma to carcinoma) - Associated with chromosomal segregation genes BUB and MAD, (and DNA repair genes
ATR/ATM, telomeres, 18q LOH?)
CIMP (CpG Island Methylator Phenotype) - Methylated promoters include TIMP3 (MMP inhibitor), MINT1/31 (MINT31 interacts with CDKN1A for cell cycle arrest - CDK inhibition), RUNX3 (TF for EGFR and MMP9), ID4 — CDKN2A and MLH1
MSI (Microsatellite Instability) - Affects genes which are known to dimerise to excise and repair DNA mismatches - MSH2+MSH6, MLH1+PMS2 - Can be inherited (Lynch syndrome/HNPCC - germline mutations in these genes, especially MSH2/6) or sporadic CRC (CIMP-induced MLH1 promoter methylation -> Loss of MLH1 induces MSI in the other MMR genes as well)
Colorectal cancer - Common checkpoint interactions for immunotherapy
CD80/CTLA4 and PD-L1/PD1
Symptoms of liver disease
Jaundice, malaise, change in stool color, pruritus, advanced - oedema, ascites, bleeding, coma
ALSO:
Gynecomastia - Breast tissue growth in men due to hyperoestrogenism, liver makes some oestrogens and metabolises/clears oestrogen
Bruising/bleeding - clotting factors
Acute liver injury
HepA/B/C infection
Alcohol/drugs
Bile duct obstruction
Gallstones -> Biliary colic, obstructive jaundice, pacreatitis (at ampulla), cholangitis
Cholangitis - Inflammatory infiltrate around the portal tract (lymphocytes + some eosinophils) + concentric lamellated periductal fibrosis (onionskin-like fibrosis)
Chronic liver injury
HepB/C - Chronic viral hepatitis
Alcoholic liver disease
Autoimmune
Primary biliary cirrhosis - More common in women, destruction of bile ducts due to anti-mitochondrial antibody + Progressive jaundice
Autoimmune hepatitis - More common in women, destruction of liver cells due to anti-nuclear and anti-smooth muscle antibodies
Haemochromatosis, NASH, Wilson’s, a-1-antitrypsin deficiency
Hepatic cirrhosis - Fibrosis, replacement of normal liver tissue with parenchymal nodules -> Portal hypertension, liver failure, hepatocellular carcinoma
HepB/C
‘Ground glass’ appearance, more homogenous and eosinophilic cytoplasm in infected hepatocytes compared to normal ones
Alcoholic liver disease - Histopathological features
Fat infiltrate, Mallory’s hyalin (highly eosinophilic, pink - ubiquitinated intermediate keratin filaments), and some immune infiltrate
Benign and malignant ‘-omas’
Benign - chondroma, lipoma, adenoma, most meningiomas, hemangioma (blood vessels in the skin), papilloma
Malignant - Lymphoma, melanoma, sarcoma, myeloma - especially MM - some can be benign, some gliomas, neuroblastoma, retinoblastoma, carcinoma
Also benign names can be made malignant, e.g. chondrosarcoma, liposarcoma
Carcinoma, with example structures
Malignant epithelial cell tumour from any of the layers - ectodermal (epidermis), mesodermal (kidney tubules), endodermal (cells lining GI tract)
Eponymous tumours
Wilms tumour (nephroblastoma), Hodgkin’s lymphoma, Ewings sarcoma, Kaposi sarcoma (autoeponymous if the person naming it had the disease)
Germ cell tumour types
Teratoma - More embryonic cells
OR
Dermoid cysts - More mature, essentially adult, cells - More cystic
Seminoma
Non-seminomatous germ cell tumours (NSGCT)
Embryonal cell carcinoma
Choriocarcinoma
Yolk sac tumour
Teratoma
Mixed germ cell tumour
SRBCTs - Types
Usually pediatric malignant neoplasms:
Desmoplastic small-round-cell tumour
Ewing sarcoma/pPNET
Rhabdomyosarcoma
Synovial sarcoma
Carcinoids
Mesothelioma
Medullo-/retino-/neuroblastoma
SRBCT - Translocations
EWSR1 gene translocations -> Ewing’s sarcoma, clear cell sarcoma, desmoplastic small round cell tumor and myxoid liposarcoma.
-> Ewing sarcoma family - EWSR1-FLI1- >90% of cases - t(11;22)(q24;q12) [OR] EWSR1 to ERG,ETV1,E1AFandFEV
-> Clear cell sarcoma, DSRCT and myxoid liposarcoma - EWS fused toATF1,WT1andCHOP respectively
-> CIC-DUX4 fusion is the most common in EWSR1/FUS-negative undifferentiated SRCTs
-> RMS - PAX3/7-FKHR (FKHR == FOXO1)
-> Synovial sarcoma - SYT-SSX
-> Mesenchymal chondrosarcoma (axial skeleton, craniofacial bones) - HEY1 (exon4)-NCOA2 (exon 13) at mRNA level
EWS - “Ewing-like sarcoma”
EWS can be confused for other neoplasms with similar immunotypic characteristics, but these lack the pathognomic mark of EWSR1 or FUS fusion with a ETS-family TF gene, for example - cancers involving EWSR1-NFATc2 or FUS-NFATc2 fusion. NFATc2 is not an ETS family member.
Philadelphia chromosome
In CML
t(9;22)(q34;q11) - BCR (B cell receptor)-ABL1(Abelson murine leukemia virus 1 - Tyr kinase) -> Constitutively active ABL kinase activates growth proteins
Lung cancer - Drugs against each mutation
EGFR - Erlotinib, Gefitinib
ALK - Crizotinib
PDL1 - Pembrolizumab
ROS1 - Crizotinib, Entrectinib
SC lung cancer - Other treatments
Most chemotherapies and VEGF/EGFR/c-Kit/c-Src inhibitors so far have been found ineffective
Antibody-drug conjugates are promising - DLL3 delta-like protein fused to pyrrolobenzodiazepine dimer toxin
Immune checkpoint inhibitors
anti-CTLA4: CTLA4 competes with CD28 to bind B7 ligands on activated APCs (co-stimulation), CTLA4 binding inhibits T cell activation -> Ipsilimumab (Yervoy) - Anti-CTLA4 to enhance T cell activity in cancer
PD-1: On surface of T, B, NK cells, interacts with PDL-1 ligands on normal host cells -> T cell apoptosis -> Prevents autoimmunity -> Also enhances immune escape in cancer cells -> Nivolumab (Opdivo), Pembrolizumab
Lung cancer - KRAS/TP53 pathways
KRAS-GDP -> KRAS-GTP
RAF/MEK/ERK, RAL/NFkB, PI3K/AKT/mTOR
mutant KRAS -> Hyperproliferative stress -> E2F1 -> ARF
Inhibits mdm2, which inhibits TP53 -> TP53 up
TP53 -> 14-3-3-s, CDKN1A, miR-34a for growth arrest
-> Bax, Fas, ig3 for apoptosis
-> Xpc, Ercc5 for DNA repair
-> CDKN1A, Pai1, Pml for Senescence
Nicotine and nitrosamines in smoking - Effects, gene alterations
Nicotine and tobacco-specific nitrosamines can directly bind and activate Akt and PKA without needing enzymatic activation
Common variants in CHRNA5/3/4 NAChR subunit gene cluster on Chr 15q25 -> More addiction, increased nicotine and NNK carcinogen uptake -> LC risk
CYP2A6 polymorphisms -> Gene for nicotine metabolism catalysis -> significant effect on smoking behaviour and LC risk
Tobacco smoke carcinogens
Polycyclic aromatic hydrocarbons (PAHs) - All genotoxic carcinogens, enzymatically activated to DNA-reactive intermediates like bay region diol epoxides
NNK - DNA-binding diazohydroxides -> KRAS mutagen
Volatiles - e.g. 1,3-butadiene and ethylene oxide
Cadmium and Po210
Breast cancer - DCIS, LCIS and Invasive BC differences (including histopathology)
DCIS - Good prognosis usually, lumpectomies tend to be curative, low recurrence
LCIS - Worse prognosis, likely to recur and become bilateral (if unilateral)
Invasive BC - Invasive cells lack E-cadherin for clumping. invade in ‘Indian files’ (almost single-file cells)
Breast cancer - Main risk factors
Early menstruation, late menopause -> Longer exposure to oestrogen, especially if nulliparous throughout this
Obesity -> More peripheral tissue, and so aromatase conversion of androgens to oestrogen (+ diabetes lowers hepatic SHBG production and secretion)
Genes involved in Barret’s oesophagus metaplasia
Irritation, especially from bile acids, triggers inflammation in Barret’s. Activation of immune cells like T cells in repeated or chronic inflammation can lead to genetic changes like:
Upreg. of CDX2 - Intestinal differentiation factor
MUC2 - Goblet cell-related gene
And alterations in p16 - 90% of cases (CDKN2A, cell cycle checkpt.)
These changes occurring in stem cells - embryonic-derived or MSC-like in lamina propria of oesophagus - triggers Barret’s metaplasia: STRAT SQUAM -> COLUMNAR (GLANDULAR-LIKE)
Gastritis findings and classification
Red mucosa, coarser and flatter, inflammatory infiltrate
Sydney classification -
Acute gastritis - Mucosal injury from alcohol/NSAIDs, corrosives, infection (S. aureus), stress (ischemia) - Acute inflammation with or without ulcers
Chronic - Inflammation of lamina propria and mucosal atrophy, often leading to epithelial metaplasia; H. pylori or autoimmune causes (anti-Parietal cells)
Heartburn (pyrosis) and dyspepsia
Pyrosis - Gastric reflux, alcohol, smoking, large meals, posture… Or oesophagitis?
Dyspepsia/indigestion - Epigastric pain , can be from gastric/duodenal ulcer, usually with nausea
Chronic lower GI pain and ischemic bowel
Obstruction (tumour), IBD, ischemic bowel (recurrent acute)
Ischemic bowel
Clots in superior (SMA, lower duodenum to 2/3 of trans. colon) or inferior mesenteric artery (IMA, distal 1/3 of trans. colon to rectum)
>75% reduction in flow for 12+ hrs, or collateral circulation will compensate
MI, arrythmia, aneurysm, atheroma, injury-induced thrombosis, coagulopathy
GI bleeding causes
Inflammation, diverticulitis/osis, polyps, cancer, NSAID overuse(?)
Oesophageal cancer
Insidious growth, usually well-established at diagnosis; can spread through oesophageal wall
Spread through adventitial tissue indicates poor survival (>20%, in 5 yrs)
Endoscopic mucosal resection if under a few cm in size, otherwise radio/resection
Gastric cancer
Most common cancer of upper GI
DIET: Nitrates (water, food - from fertilizers) -> Bacterial metabolism -> Nitrites -> Nitrosation of dietary amines -> Carcinogenic N-nitrosamines
Also - smoking, alcohol, asbestos, blood type A
Gastric ulcers
Occur when acid erodes the mucosa. Can present with epigastric pain, dyspepsia, nausea, hematemesis OR be asymptomatic. About 10% are malignant, or 40% if over 2cm in diameter.
H. pylori can cause ulcers by damaging the mucus lining of the stomach, by (digestion? or) inflammation, then allowing acid erosion of the mucosa.
MALToma
Mucosa-associated lymphoid tissue lymphoma
In H. pylori infection, chemokines recruit T cells and immune cells for inflammation (ROS) - this can also lead to epigenetic (esp. miRNA) alterations. The CagA antigen of HP can also enter B cells, wherein it upregulates p53, Bcl-2, Bcl-XL and inhibits apoptosis.
CRC risk factors
Red, processed and fried meats; low vit. D; obesity; T2D; IBD; history of GI surgery or family history of CRC or Lynch syndrome
CRC - KRAS mutations in EGFR treatment
KRAS mutation can make EGFR treatments futile, as KRAS would be active independent of upstream EGFR activation
