godfather of surgery

Chapter 1283 Atypical Pain
Yang Ping had no interest in Huang Jiacai's business battles, nor did he want to get involved. He continued to see patients at the research institute's outpatient clinic as usual.

He had just finished a multinational video consultation regarding a complex spinal case involving a member of Middle Eastern royalty. He took a sip of tea and nodded to Dr. Li Min beside him: "Next."

The patient who entered was a woman in her thirties, surnamed Lin. She wasn't pushed in a wheelchair, nor did she walk unsteadily; she walked in on her own, her gait even light and brisk. She was dressed impeccably in a beige cardigan and trousers, her makeup was exquisite, and her hair was neatly tied up. She carried only a slim tablet and a minimalist handbag, a stark contrast to the patients in the waiting area who carried heavy imaging bags.

Yang Ping's gaze swept across her face. She only appeared healthy; the overly perfect makeup concealed a weariness that emanated from her very bones, and a numbness deep within her eyes—a state of mind characteristic of those suffering from chronic pain.

"Professor Yang, hello, I'm sorry to bother you with your precious time." Ms. Lin's voice was soft and clear, with the restraint she had developed through her professional training.

"Ms. Lin, please sit down. Are you feeling unwell?" Yang Ping's tone was as calm as ever.

She sat very upright, almost entirely maintained by her back muscles, avoiding completely relaxing and leaning back in the chair.

Ms. Lin turned on her tablet, pulled up an electronic medical record summary, and handed it to Li Min with a smooth motion. "I've had intermittent, migratory pain in my lower back and many bones throughout my body for about five years, and it's gotten much worse in the last six months."

"Describe the pain in detail? In which areas is it most pronounced? What is its nature? For example, how does the pain feel: like needle pricks, cutting, burning, etc." Yang Ping asked, while gesturing for Li Min to synchronize the data on the tablet to the screen in the consultation room.

"At first, I had a soreness in my lower back, which I thought was caused by poor posture. Later, the pain would move to my left scapula, right ribcage, left hip, and sometimes even the bones of my shin. It felt like the pain was inside the bones. I can't describe this kind of pain. Sometimes it felt like being slowly drilled." Her description was very precise, without much emotional embellishment. "There was no obvious redness, swelling, or heat. The pain attacks were not absolutely regular, but they seemed to be easily triggered by fatigue, stress, or changes in weather. Rest could relieve it somewhat, but it could not completely eliminate it."

Li Min had quickly browsed through the electronic medical records. The examination records were vast: consultation records from rheumatology, pain management, orthopedics, and even hematology departments of several top domestic and international hospitals. The laboratory test section was astonishingly long: complete blood count, a full set of inflammatory markers (erythrocyte sedimentation rate, CRP), autoimmune antibody profile (from common ANA, RF, and anti-CCP to rare anti-MDA5 and anti-TIF1-γ), tumor markers, immunofixation electrophoresis, bone metabolism markers, heavy metal screening... The vast majority were negative or within the normal range. Occasionally, there were slight increases in erythrocyte sedimentation rate or CRP, but these were far from reaching the level required to diagnose typical inflammatory diseases.

The imaging data was even more alarming: X-rays, CT scans, MRIs, and even PET-CT scans of multiple parts of the body. The imaging findings were indeed present, but extremely selective and discrete: slightly roughened cortical bone with mild bone marrow edema at the posterior end of the left third rib; suspicious microcystic changes under the iliac bone surface of the right sacroiliac joint; punctate fat deposits under the endplates of multiple lumbar vertebrae; abnormal signal at the attachment point of the tendon beside the greater trochanter of the left femur… Each finding seemed scattered and of unclear significance, unable to form a clear chain of evidence for the disease. The PET-CT scan showed slight increased metabolism in some painful areas, but the SUVmax value was very low. The radiology department concluded that it was a “non-specific change, possibly related to local degeneration or mechanical stimulation.”

“You’ve had many tests done and seen many doctors.” Yang Ping’s gaze shifted from the screen back to Ms. Lin’s face. “Did they give any biased diagnoses or treatment suggestions?”

Ms. Lin's smile faded slightly, revealing a hint of bitterness: "There have been many diagnoses, but none of them are certain. For example, undifferentiated connective tissue disease, fibromyalgia syndrome, somatic pain disorder, chronic fatigue syndrome with osteoarthritis... We also suspected very early-stage ankylosing spondylitis, but HLA-B27 was negative, and the sacroiliac joint imaging did not support it. We also ruled out the possibility of myeloma and bone metastases."

Clearly, she has extensive medical experience, and she delivered these diagnoses very fluently and accurately.

"What about treatment?" Yang Ping continued to ask.

Ms. Lin answered without hesitation: “I’ve tried many things. Nonsteroidal anti-inflammatory drugs (NSAIDs) have limited effects and are bad for the stomach; low-dose prednisone, I tried it for a month, and the pain seemed to improve slightly, but over time the side effects made me swollen and moody, and I quickly returned to normal after stopping it; various medications for regulating neuralgia, such as gabapentin and pregabalin, had little effect and made me feel drowsy; the antidepressant duloxetine helped my mood a little, but the bone pain persisted. Physical therapy, acupuncture, bone setting… the effects were short-lived, and some were simply useless.” She listed them clearly and calmly, obviously having repeated them countless times. “Recently, a German expert suspected it was an extremely rare subtype of chronic nonbacterial osteomyelitis and suggested trying long-term antibiotics or bisphosphonates, but the evidence is also insufficient, and I haven’t decided yet.”

For five years, the patient experienced migratory bone pain throughout the body, with mild objective signs, almost no abnormalities in laboratory tests, and scattered, nonspecific imaging findings. The patient also showed poor response to various treatments. This is indeed a typical case of a complex and difficult-to-treat illness.

Atypical pain occurs in many patients, but most of it is dismissed as a sub-healthy condition, with no cause found.

"Besides bone pain, are there any other discomforts? For example, fever, rash, mouth ulcers, hair loss, dry mouth and eyes, diarrhea, recurrent infections?" Yang Ping pressed on, because he had determined that the patient had sufficient comprehension ability, so his questions became more concise.

Ms. Lin thought about it carefully and shook her head: "No, I don't have any of those. I sleep poorly because of the pain, I have very little energy, and I get tired easily, but my body temperature is normal, I don't have any rashes or ulcers, my digestion is normal, and I don't catch colds very often."

Have you been injured? For example, in a car accident or a fall?

"No."

"Occupation? Special hobbies? Have you been exposed to chemicals or heavy metals? Do you keep pets?" Yang Ping's questions began to expand.

"I am an architect, working in an office. My hobbies are gardening and painting, especially watercolor painting. I have no special contact with chemicals, and I have had a cat at home for many years."

"Do any immediate family members have similar pain problems, or a history of autoimmune diseases or tumors?"

"No."

The diagnostic approach is essentially a process of narrowing down the scope of investigation, often starting with common and frequently occurring diseases and gradually moving towards less common and rare diseases.

Gradually, the consultation seemed to have reached a stalemate, and all the conventional approaches had led to dead ends.

Yang Ping stood up: "I need to give you a physical examination."

Ms. Lin relaxed and lay down on the examination bed.

Yang Ping's physical examination was meticulous. He pressed on all the areas of pain she described: the costochondrial junction, the medial border of the scapula, the paravertebral muscles, the greater trochanter, the anterior border of the tibia... Her reactions were consistent: a slight frown, indicating deep tenderness, but not unbearable pain. Joint range of motion was completely normal, with no swelling, fever, or crepitus. Neurological examination: muscle strength, sensation, and reflexes were all symmetrical and normal; the straight leg raise test was negative.

Everything seemed inconsistent with her description of five years of "crackling" pain that impacted her quality of life. This could easily lead to a diagnosis of "psychogenic" or "central sensitization."

But Yang Ping did not jump to conclusions. He believed that all pain had a cause, it was just that the cause had not yet been found.

His fingers gently touched the area at the back of her left third rib, where there was a slight abnormality on the imaging, and then, instead of simply pressing, his fingertips made a very subtle, rotating, grinding motion.

"Uh..." Ms. Lin suddenly took a breath, her body tensing up almost imperceptibly for a moment.

This reaction was more pronounced than simply pressing, and Yang Ping noticed it.

He followed the same procedure, palpating several points on imaging that showed subtle signal changes, such as the iliac bone surface of the right sacroiliac joint and the area next to the greater trochanter of the left femur, and applying slight stress in different directions. Ms. Lin responded more sensitively to these stress palpates than to simple pressure.

This is subtle, but important, suggesting that pain may indeed be related to the “fragility” or “instability” of these local, microscopic structures of the bones, rather than just soft tissue or nerve sensitization.

Yang Ping finished the physical examination, washed his hands, and sat back down, lost in thought as he stared at the MRI images. Li Min waited, holding his breath. Yang Ping's gaze swept over every detail in the magnified MRI images showing mild bone marrow edema or cortical irregularities. His brain was rapidly processing the information: multi-site, asymmetrical, migratory pain in the bones themselves, not joint pain; extremely low objective inflammatory markers; extremely mild, discrete bone structural changes on imaging, such as edema, microcystic changes, and cortical irregularities; poor response to conventional anti-inflammatory and neuromodulation treatments; physical examination suggesting the pain was related to localized stress in the bones…

A vague outline began to emerge in his mind, an outline that didn't belong to common arthritis, spondyloarthritis, metabolic bone disease, tumors, or infections. It was more like a problem with the quality or stability of the bone itself, leading to microscopic damage and poor repair in certain localized areas under normal or slightly increased loads, and abnormally amplified pain signals. But what could cause the bone to become so widely and selectively brittle?

Common types of osteoporosis?
Her bone density test report showed that her T-score was within the normal range, which was inconsistent with her age, and the nature of her pain was also atypical.

Hereditary bone disease? Such as osteogenesis imperfecta? But without blue sclera, no history of multiple fractures, and no typical "football shirt" spine on imaging.

After careful consideration, a rarer and more hidden possibility gradually emerged in my mind.

This possibility could explain why laboratory tests are so clean—because it may not involve typical immune inflammatory pathways at all; it could also explain why imaging changes are so subtle and discrete—because the lesions may be at the molecular or microstructural level; and it could also explain why the pain is so prominent yet treatment is ineffective—because the underlying cause has not been addressed.

This possibility points to a type of disease often overlooked by orthopedic surgeons: abnormal mineral metabolism or subtle imbalances in the synthesis or degradation of bone matrix.

“Ms. Lin,” Yang Ping began, breaking the silence, “do you usually drink milk, take calcium tablets, or vitamin D supplements?”

"I drink milk occasionally, and I took calcium and vitamin D supplements for about six months, but I didn't stick to it. At the time, I heard from a doctor that women should take preventative measures against osteoporosis, so I took them for a while," Ms. Lin replied.

Do you have any chronic gastritis, such as atrophic gastritis? Or have you been taking acid-suppressing medications, such as omeprazole, for a long time?

"My stomach occasionally feels uncomfortable, but I haven't been diagnosed with gastritis, and I rarely take antacids."

Do you have chronic diarrhea, steatorrhea, or any problems with your pancreas, liver, or gallbladder?

"nothing."

"When you do gardening, do you grow flowers or vegetables? What kind of fertilizer do you use? Are the watercolor paints you use professional-grade or children's grade? Do you have any particular brands or color preferences?" Yang Ping's questions once again turned to seemingly unrelated details.

Ms. Lin was a little confused, but still answered: "I mainly grow succulents and foliage plants, using ordinary compound fertilizer and potting soil. The watercolors are professional-grade Winsor & Newton. As for the colors? I use cobalt blue and cadmium red most often to paint the sky and sunset."

Cobalt blue, cadmium red? A sharp glint flashed in Yang Ping's eyes as a "thread" appeared, which Yang Ping keenly grasped.

"In the last year or two, have you felt particularly tired, more so than when the pain first started five years ago? Have you noticed any weight loss? Have you felt that your attention or memory is not as good as before?" Yang Ping's questions began to focus.

Ms. Lin hesitated for a moment, her mask of composure crumbling: "...Yes, the fatigue is getting worse, and I still feel tired no matter how much I sleep. I have indeed lost three or four kilograms, even though I didn't intentionally lose weight. My memory...it seems like I sometimes forget things, and it's hard for me to concentrate. I thought it was due to the pain and poor sleep."

Have you noticed that your skin is drier or itchier than before? Or that your wounds are healing more slowly than usual?

"It seems so, my skin gets especially dry in winter. About six months ago, I cut my hand and it took more than two weeks to heal."

Li Min also sensed something unusual. These symptoms were too scattered and nonspecific; any single symptom would not attract attention, but when combined, they pointed to a potential, chronic metabolic or toxic process affecting multiple systems.

“I need to arrange a few new tests for you,” Yang Ping said, his tone becoming serious. “These tests may not be part of the routine screening, but they may be crucial in clarifying your condition.”

"A follow-up examination and more comprehensive mineral and trace element tests should be conducted: not only should blood calcium, blood phosphorus, and alkaline phosphatase be checked, but also blood magnesium, blood copper, blood zinc, blood cobalt, blood cadmium, and blood lead, as well as 24-hour urinary calcium, urinary phosphorus, urinary magnesium, urinary cobalt, and urinary cadmium." He specifically emphasized cobalt and cadmium.

Ms. Lin's face paled slightly when she heard that the ingredients of the pigments she often used were being tested.

"Detect serum parathyroid hormone (PTH)-related peptide, vitamin D metabolites, especially 1,25-dihydroxyvitamin D, and fibroblast growth factor 23 (FGF23)." These are involved in a complex calcium and phosphorus metabolism regulatory axis.

“Reassess bone turnover indicators, especially markers that are more sensitive to bone formation and bone resorption, such as P1NP and β-CTX.”

"I recommend an iliac bone biopsy for bone histomorphometric analysis, which is the gold standard for assessing bone microstructure and bone turnover status. Although it is an invasive procedure, it may be necessary if blood tests indicate a positive result."

Yang Ping looked at Ms. Lin: "Your condition may not be a typical case of certain types of arthritis or autoimmune diseases. The root cause of the pain may lie in a very subtle and hidden problem in the internal environment of the bones themselves, such as a disorder of some mineral metabolism, or chronic exposure to certain elements at extremely low levels interfering with normal bone metabolism. The pigment you mentioned is a clue that needs to be ruled out. Of course, it could also be other undiscovered endocrine or genetic factors."

Ms. Lin completely abandoned her professional smile, her face revealing a mixture of anticipation and nervousness—the first time in five years she had come so close to the truth. "Professor Yang, are you saying it might be poisoning? Or perhaps there's too much or too little of something in your body?"

“This is one possibility, and it’s one that can be detected and intervened,” Yang Ping replied cautiously. “We need to use a finer sieve to catch what might have been missed before, and this process may take time.”

"I'm willing to do it! As long as there's a glimmer of hope to find out the truth, I'm willing to cooperate!" Ms. Lin's voice trembled slightly.

"Okay, Dr. Li, contact the laboratory, endocrinology, and occupational disease departments immediately to coordinate and arrange these special examinations. Also, discuss the possibility of a bone biopsy with the pathology and interventional radiology departments first," Yang Ping quickly instructed.

After seeing Ms. Lin off, Li Min couldn't help but ask, "Professor Yang, do you really suspect it's heavy metals? Cobalt or cadmium? But her exposure should be very mild, and it was transdermal?"

“Mild, chronic exposure is sometimes harder to detect than acute poisoning, and the symptoms are more subtle and varied. Cobalt can affect mitochondrial function, leading to unexplained fatigue, neurological symptoms, and even cardiomyopathy; cadmium accumulation mainly damages the kidneys and bones, causing calcium and phosphorus metabolism disorders and bone pain. She used professional pigments, and although transdermal absorption is limited, long-term and frequent exposure, coupled with possible individual susceptibility, such as increased skin permeability after sweating, or extremely minor wounds, cannot be completely ruled out. More importantly,” Yang Ping pointed to the discrete abnormal bone signals on the screen, “these areas are where muscles and tendons attach frequently, where stress is relatively concentrated, or where blood supply is special. If bones become brittle for some reason, these areas are the weakest links, and they are the first to show microscopic damage and pain. Our routine bone density test reflects bone volume, not bone quality. Her problem may lie precisely in bone quality.”

He paused for a moment: "In medicine, when all the common pathways pointing to a specific disease are blocked, we have to look back and examine the most basic life processes: cellular energy metabolism, mineral balance, and the synthesis and degradation of the matrix. Subtle disturbances in these processes are often overlooked by broad disease classifications, but they are enough to plunge a person into long-term suffering. Our task is to find that disturbance, even if it is deeply hidden."

"Furthermore, we often overlook patients with atypical pain, always attributing it to fatigue, old age, lack of rest, and so on. In short, we tend to be perfunctory about this kind of pain most of the time. Li Min, if you can treat atypical pain well, your skill level will reach a new level."

Li Min kept Professor Yang's words in mind.